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Androgen Receptors in the Pathology of Disease

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Nuclear Receptors

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Abstract

Androgen receptor (AR) belongs to the steroid hormone receptor group of ligand-activated transcription factors in the nuclear receptor superfamily. AR mediates the action of physiological and exogenous androgens to regulate the expression of a network of genes in target tissues that are essential for the development and maintenance of the male phenotype and reproductive function as well as the function of numerous other tissues in both males and females. AR is ubiquitously expressed throughout the body. AR is a modular protein that comprises an N-terminal domain (NTD) that contains all of its transcriptional activity, a DNA-binding domain, a flexible hinge region, and a C-terminal ligand-binding domain (LBD). All clinically approved hormonal therapies target the AR LBD, either directly with antiandrogens and selective AR modulators or indirectly by reducing levels of androgens. Pathological conditions related to AR dysfunction involve altered levels of androgens and structural alterations in the AR. These include mutations, polymorphisms in the polyglutamine tract of the NTD, and alternative splicing of AR to yield constitutively active receptors. From the extensive list of AR-related diseases, herein we describe prostate cancer, androgen-insensitivity syndrome, polycystic ovary syndrome, breast cancer, and a few more pathological conditions in more detail.

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Abbreviations

AF-1:

activation function 1

AF-2:

activation function 2

AR:

androgen receptor

ARKO:

AR knockout

AR-Vs:

androgen receptor splice variants

CAIS:

complete androgen insensitivity syndrome

CRPC:

castration-resistant prostate cancer

CTCs:

circulating tumor cells

CTE:

C-terminal extension

DBD:

DNA-binding domain

DHEA:

dehydroepiandrosterone

DHT:

5α-dihydrotestosterone

E2:

17β-estradiol

EMS:

external masculinization score

ER:

estrogen receptor

fl-AR:

full-length AR

GR:

glucocorticoid receptor

HSP:

heat-shock protein

KLK3/PSA:

prostate-specific antigen

LBD:

ligand-binding domain

LH:

luteinizing hormone

LH-RH:

luteinizing hormone-releasing hormone

MAIS:

mild androgen insensitivity syndrome

NTD:

N-terminal domain

PAIS:

partial androgen insensitivity syndrome

PCOS:

polycystic ovary syndrome

PR:

progesterone receptor

SARM:

selective androgen receptor modulator

SBMA:

spinal-bulbar muscular atrophy

SHBG:

sex-hormone-binding globulin

TAU:

transactivation unit

TNBC:

triple-negative breast cancer

References

  1. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA guideline. J Urol. 2018;200(2):423–32. https://doi.org/10.1016/j.juro.2018.03.115.

    Article  PubMed  Google Scholar 

  2. Dunn JF, Nisula BC, Rodbard D. Transport of steroid hormones: binding of 21 endogenous steroids to both testosterone-binding globulin and corticosteroid-binding globulin in human plasma. J Clin Endocrinol Metab. 1981;53(1):58–68. https://doi.org/10.1210/jcem-53-1-58.

    Article  CAS  PubMed  Google Scholar 

  3. Winters SJ. Laboratory assessment of testicular function. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA). (Updated 2020 Feb 29). MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279145/.

  4. Page ST, Lin DW, Mostaghel EA, et al. Persistent intraprostatic androgen concentrations after medical castration in healthy men. J Clin Endocrinol Metab. 2006;91(10):3850–6. https://doi.org/10.1210/jc.2006-0968.

    Article  CAS  PubMed  Google Scholar 

  5. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002;20(13):3001–15. https://doi.org/10.1200/JCO.2002.10.018.

    Article  CAS  PubMed  Google Scholar 

  6. Ruizeveld de Winter JA, Trapman J, Vermey M, et al. Androgen receptor expression in human tissues: an immunohistochemical study. J Histochem Cytochem. 1991;39(7):927–36. https://doi.org/10.1177/39.7.1865110.

    Article  CAS  PubMed  Google Scholar 

  7. Uhlen M, Fagerberg L, Hallstrom BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. https://doi.org/10.1126/science.1260419.

    Article  CAS  PubMed  Google Scholar 

  8. Werner CK, Nna UJ, Sun H, et al. Expression of the of the androgen receptor governs radiation resistance in a subset of glioblastomas vulnerable to anti-androgen therapy. Mol Cancer Ther. 2020; https://doi.org/10.1158/1535-7163.MCT-20-0095.

  9. Miller CP, Shomali M, Lyttle CR, et al. Design, synthesis, and preclinical characterization of the Selective Androgen Receptor Modulator (SARM) RAD140. ACS Med Chem Lett. 2011;2(2):124–9. https://doi.org/10.1021/ml1002508.

    Article  CAS  PubMed  Google Scholar 

  10. McEwan IJ, Smith LB. Androgen receptor. Academic Press; 2018.

    Book  Google Scholar 

  11. Burnstein KL. Regulation of androgen receptor levels: implications for prostate cancer progression and therapy. J Cell Biochem. 2005;95(4):657–69. https://doi.org/10.1002/jcb.20460.

    Article  CAS  PubMed  Google Scholar 

  12. Hunter I, Hay CW, Esswein B, et al. Tissue control of androgen action: the ups and downs of androgen receptor expression. Mol Cell Endocrinol. 2018;465:27–35. https://doi.org/10.1016/j.mce.2017.08.002.

    Article  CAS  PubMed  Google Scholar 

  13. Banuelos CA, Lal A, Tien AH, et al. Characterization of niphatenones that inhibit androgen receptor N-terminal domain. PLoS One. 2014;9(9):e107991. https://doi.org/10.1371/journal.pone.0107991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Matias PM, Donner P, Coelho R, et al. Structural evidence for ligand specificity in the binding domain of the human androgen receptor. Implications for pathogenic gene mutations. J Biol Chem. 2000;275(34):26164–71. https://doi.org/10.1074/jbc.M004571200.

    Article  CAS  PubMed  Google Scholar 

  15. Cleutjens CB, Steketee K, van Eekelen CC, et al. Both androgen receptor and glucocorticoid receptor are able to induce prostate-specific antigen expression, but differ in their growth-stimulating properties of LNCaP cells. Endocrinology. 1997;138(12):5293–300. https://doi.org/10.1210/endo.138.12.5564.

    Article  CAS  PubMed  Google Scholar 

  16. Sahu B, Laakso M, Pihlajamaa P, et al. FoxA1 specifies unique androgen and glucocorticoid receptor binding events in prostate cancer cells. Cancer Res. 2013;73(5):1570–80. https://doi.org/10.1158/0008-5472.CAN-12-2350.

    Article  CAS  PubMed  Google Scholar 

  17. Claessens F, Joniau S, Helsen C. Comparing the rules of engagement of androgen and glucocorticoid receptors. Cell Mol Life Sci. 2017;74(12):2217–28. https://doi.org/10.1007/s00018-017-2467-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer. 2014;5(2):72–89. https://doi.org/10.1007/s12672-014-0173-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Puhr M, Hoefer J, Eigentler A, et al. The glucocorticoid receptor is a key player for prostate cancer cell survival and a target for improved antiandrogen therapy. Clin Cancer Res. 2018;24(4):927–38. https://doi.org/10.1158/1078-0432.CCR-17-0989.

    Article  CAS  PubMed  Google Scholar 

  20. Kumar R, Betney R, Li J, et al. Induced alpha-helix structure in AF1 of the androgen receptor upon binding transcription factor TFIIF. Biochemistry. 2004;43(11):3008–13. https://doi.org/10.1021/bi035934p.

    Article  CAS  PubMed  Google Scholar 

  21. Reid J, Kelly SM, Watt K, et al. Conformational analysis of the androgen receptor amino-terminal domain involved in transactivation. Influence of structure-stabilizing solutes and protein-protein interactions. J Biol Chem. 2002;277(22):20079–86. https://doi.org/10.1074/jbc.M201003200.

    Article  CAS  PubMed  Google Scholar 

  22. Davis-Dao CA, Tuazon ED, Sokol RZ, et al. Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab. 2007;92(11):4319–26. https://doi.org/10.1210/jc.2007-1110.

    Article  CAS  PubMed  Google Scholar 

  23. Ellis JA, Stebbing M, Harrap SB. Polymorphism of the androgen receptor gene is associated with male pattern baldness. J Invest Dermatol. 2001;116(3):452–5. https://doi.org/10.1046/j.1523-1747.2001.01261.x.

    Article  CAS  PubMed  Google Scholar 

  24. Giovannucci E, Stampfer MJ, Chan A, et al. CAG repeat within the androgen receptor gene and incidence of surgery for benign prostatic hyperplasia in U.S. physicians. Prostate. 1999;39(2):130–4. https://doi.org/10.1002/(sici)1097-0045(19990501)39:2<130::aid-pros8>3.0.co;2-#.

    Article  CAS  PubMed  Google Scholar 

  25. Baculescu N. The role of androgen receptor activity mediated by the CAG repeat polymorphism in the pathogenesis of PCOS. J Med Life. 2013;6(1):18–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature. 1991;352(6330):77–9. https://doi.org/10.1038/352077a0.

    Article  PubMed  Google Scholar 

  27. Mao Q, Qiu M, Dong G, et al. CAG repeat polymorphisms in the androgen receptor and breast cancer risk in women: a meta-analysis of 17 studies. Onco Targets Ther. 2015;8:2111–20. https://doi.org/10.2147/OTT.S85130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mizushima T, Miyamoto H. The role of androgen receptor signaling in ovarian cancer. Cells. 2019;8(2) https://doi.org/10.3390/cells8020176.

  29. Nelson KA, Witte JS. Androgen receptor CAG repeats and prostate cancer. Am J Epidemiol. 2002;155(10):883–90. https://doi.org/10.1093/aje/155.10.883.

    Article  PubMed  Google Scholar 

  30. Giovannucci E, Stampfer MJ, Krithivas K, et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A. 1997;94(7):3320–3. https://doi.org/10.1073/pnas.94.7.3320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. He B, Bai S, Hnat AT, et al. An androgen receptor NH2-terminal conserved motif interacts with the COOH terminus of the Hsp70-interacting protein (CHIP). J Biol Chem. 2004;279(29):30643–53. https://doi.org/10.1074/jbc.M403117200.

    Article  CAS  PubMed  Google Scholar 

  32. He B, Bowen NT, Minges JT, et al. Androgen-induced NH2- and COOH-terminal interaction inhibits p160 coactivator recruitment by activation function 2. J Biol Chem. 2001;276(45):42293–301. https://doi.org/10.1074/jbc.M107492200.

    Article  CAS  PubMed  Google Scholar 

  33. He B, Kemppainen JA, Wilson EM. FXXLF and WXXLF sequences mediate the NH2-terminal interaction with the ligand binding domain of the androgen receptor. J Biol Chem. 2000;275(30):22986–94. https://doi.org/10.1074/jbc.M002807200.

    Article  CAS  PubMed  Google Scholar 

  34. Yu X, Yi P, Hamilton RA, et al. Structural insights of transcriptionally active, full-length androgen receptor coactivator complexes. Mol Cell. 2020;79(5):812–823 e814. https://doi.org/10.1016/j.molcel.2020.06.031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ueda T, Mawji NR, Bruchovsky N, et al. Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells. J Biol Chem. 2002;277(41):38087–94. https://doi.org/10.1074/jbc.M203313200.

    Article  CAS  PubMed  Google Scholar 

  36. Chen SY, Wulf G, Zhou XZ, et al. Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. Mol Cell Biol. 2006;26(3):929–39. https://doi.org/10.1128/MCB.26.3.929-939.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. La Montagna R, Caligiuri I, Maranta P, et al. Androgen receptor serine 81 mediates Pin1 interaction and activity. Cell Cycle. 2012;11(18):3415–20. https://doi.org/10.4161/cc.21730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leung JK, Imamura Y, Kato M, et al. Targeting Pin1 improves the efficacy of ralaniten compounds that bind to the intrinsically disordered N-terminal domain of androgen receptor. Submitted. 2020.

    Google Scholar 

  39. Shaffer PL, Jivan A, Dollins DE, et al. Structural basis of androgen receptor binding to selective androgen response elements. Proc Natl Acad Sci U S A. 2004;101(14):4758–63. https://doi.org/10.1073/pnas.0401123101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Claessens F, Alen P, Devos A, et al. The androgen-specific probasin response element 2 interacts differentially with androgen and glucocorticoid receptors. J Biol Chem. 1996;271(32):19013–6. https://doi.org/10.1074/jbc.271.32.19013.

    Article  CAS  PubMed  Google Scholar 

  41. Dahlman-Wright K, Wright A, Gustafsson JA, et al. Interaction of the glucocorticoid receptor DNA-binding domain with DNA as a dimer is mediated by a short segment of five amino acids. J Biol Chem. 1991;266(5):3107–12.

    Article  CAS  PubMed  Google Scholar 

  42. Haelens A, Verrijdt G, Callewaert L, et al. DNA recognition by the androgen receptor: evidence for an alternative DNA-dependent dimerization, and an active role of sequences flanking the response element on transactivation. Biochem J. 2003;369(Pt 1):141–51. https://doi.org/10.1042/BJ20020912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Clinckemalie L, Vanderschueren D, Boonen S, et al. The hinge region in androgen receptor control. Mol Cell Endocrinol. 2012;358(1):1–8. https://doi.org/10.1016/j.mce.2012.02.019.

    Article  CAS  PubMed  Google Scholar 

  44. Hill KK, Roemer SC, Churchill ME, et al. Structural and functional analysis of domains of the progesterone receptor. Mol Cell Endocrinol. 2012;348(2):418–29. https://doi.org/10.1016/j.mce.2011.07.017.

    Article  CAS  PubMed  Google Scholar 

  45. He B, Kemppainen JA, Voegel JJ, et al. Activation function 2 in the human androgen receptor ligand binding domain mediates interdomain communication with the NH(2)-terminal domain. J Biol Chem. 1999;274(52):37219–25. https://doi.org/10.1074/jbc.274.52.37219.

    Article  CAS  PubMed  Google Scholar 

  46. Jenster G, van der Korput HA, Trapman J, et al. Identification of two transcription activation units in the N-terminal domain of the human androgen receptor. J Biol Chem. 1995;270(13):7341–6. https://doi.org/10.1074/jbc.270.13.7341.

    Article  CAS  PubMed  Google Scholar 

  47. Dehm SM, Tindall DJ. Alternatively spliced androgen receptor variants. Endocr Relat Cancer. 2011;18(5):R183–96. https://doi.org/10.1530/ERC-11-0141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Paschalis A, Sharp A, Welti JC, et al. Alternative splicing in prostate cancer. Nat Rev Clin Oncol. 2018;15(11):663–75. https://doi.org/10.1038/s41571-018-0085-0.

    Article  CAS  PubMed  Google Scholar 

  49. Eisermann K, Wang D, Jing Y, et al. Androgen receptor gene mutation, rearrangement, polymorphism. Transl Androl Urol. 2013;2(3):137–47. https://doi.org/10.3978/j.issn.2223-4683.2013.09.15.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Pereira de Jesus-Tran K, Cote PL, Cantin L, et al. Comparison of crystal structures of human androgen receptor ligand-binding domain complexed with various agonists reveals molecular determinants responsible for binding affinity. Protein Sci. 2006;15(5):987–99. https://doi.org/10.1110/ps.051905906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Leung JK, Sadar MD. Non-genomic actions of the androgen receptor in prostate cancer. Front Endocrinol (Lausanne). 2017;8:2. https://doi.org/10.3389/fendo.2017.00002.

    Article  Google Scholar 

  52. van Royen ME, van Cappellen WA, de Vos C, et al. Stepwise androgen receptor dimerization. J Cell Sci. 2012;125(Pt 8):1970–9. https://doi.org/10.1242/jcs.096792.

    Article  CAS  PubMed  Google Scholar 

  53. Clapier CR, Cairns BR. The biology of chromatin remodeling complexes. Annu Rev Biochem. 2009;78:273–304. https://doi.org/10.1146/annurev.biochem.77.062706.153223.

    Article  CAS  PubMed  Google Scholar 

  54. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev. 2007;28(7):778–808. https://doi.org/10.1210/er.2007-0019.

    Article  CAS  PubMed  Google Scholar 

  55. Cheng D, Bedford MT. Xenoestrogens regulate the activity of arginine methyltransferases. Chembiochem. 2011;12(2):323–9. https://doi.org/10.1002/cbic.201000522.

    Article  CAS  PubMed  Google Scholar 

  56. Hong H, Kao C, Jeng MH, et al. Aberrant expression of CARM1, a transcriptional coactivator of androgen receptor, in the development of prostate carcinoma and androgen-independent status. Cancer. 2004;101(1):83–9. https://doi.org/10.1002/cncr.20327.

    Article  CAS  PubMed  Google Scholar 

  57. Hankey W, Chen Z, Wang Q. Shaping chromatin states in prostate cancer by pioneer transcription factors. Cancer Res. 2020;80(12):2427–36. https://doi.org/10.1158/0008-5472.CAN-19-3447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Stelloo S, Nevedomskaya E, Kim Y, et al. Endogenous androgen receptor proteomic profiling reveals genomic subcomplex involved in prostate tumorigenesis. Oncogene. 2018;37(3):313–22. https://doi.org/10.1038/onc.2017.330.

    Article  CAS  PubMed  Google Scholar 

  59. Yang YA, Yu J. Current perspectives on FOXA1 regulation of androgen receptor signaling and prostate cancer. Genes Dis. 2015;2(2):144–51. https://doi.org/10.1016/j.gendis.2015.01.003.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhao Y, Tindall DJ, Huang H. Modulation of androgen receptor by FOXA1 and FOXO1 factors in prostate cancer. Int J Biol Sci. 2014;10(6):614–9. https://doi.org/10.7150/ijbs.8389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Banuelos CA, Ito Y, Obst JK, et al. Ralaniten sensitizes enzalutamide-resistant prostate cancer to ionizing radiation in prostate cancer cells that express androgen receptor splice variants. Cancers (Basel). 2020;12(7) https://doi.org/10.3390/cancers12071991.

  62. Bolton EC, So AY, Chaivorapol C, et al. Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev. 2007;21(16):2005–17. https://doi.org/10.1101/gad.1564207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mills IG. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer. Nat Rev Cancer. 2014;14(3):187–98. https://doi.org/10.1038/nrc3678.

    Article  CAS  PubMed  Google Scholar 

  64. Romanuik TL, Wang G, Holt RA, et al. Identification of novel androgen-responsive genes by sequencing of LongSAGE libraries. BMC Genomics. 2009;10:476. https://doi.org/10.1186/1471-2164-10-476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tien AH, Sadar MD. Androgen-responsive gene expression in prostate cancer progression. In: Wang Z, editor. Androgen-responsive genes in prostate cancer. Springer; 2013. p. 135–53.

    Chapter  Google Scholar 

  66. Bhowmick NA, Oft J, Dorff T, et al. COVID-19 and androgen-targeted therapy for prostate cancer patients. Endocr Relat Cancer. 2020;27(9):R281–92. https://doi.org/10.1530/ERC-20-0165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Stopsack KH, Mucci LA, Antonarakis ES, et al. TMPRSS2 and COVID-19: serendipity or opportunity for intervention? Cancer Discov. 2020;10(6):779–82. https://doi.org/10.1158/2159-8290.CD-20-0451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Huggins C. Endocrine-induced regression of cancers. Cancer Res. 1967;27(11):1925–30.

    CAS  PubMed  Google Scholar 

  69. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22(4):232–40. https://doi.org/10.3322/canjclin.22.4.232.

    Article  CAS  PubMed  Google Scholar 

  70. Crawford ED, Heidenreich A, Lawrentschuk N, et al. Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations. Prostate Cancer Prostatic Dis. 2019;22(1):24–38. https://doi.org/10.1038/s41391-018-0079-0.

    Article  PubMed  Google Scholar 

  71. Rice MA, Malhotra SV, Stoyanova T. Second-generation antiandrogens: from discovery to standard of care in castration resistant prostate cancer. Front Oncol. 2019;9:801. https://doi.org/10.3389/fonc.2019.00801.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Chandrasekar T, Yang JC, Gao AC, et al. Targeting molecular resistance in castration-resistant prostate cancer. BMC Med. 2015;13:206. https://doi.org/10.1186/s12916-015-0457-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–28. https://doi.org/10.1016/j.cell.2015.05.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11–22. https://doi.org/10.1016/j.ccr.2010.05.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25. https://doi.org/10.1016/j.cell.2015.10.025.

    Article  CAS  Google Scholar 

  76. Koivisto P, Kononen J, Palmberg C, et al. Androgen receptor gene amplification: a possible molecular mechanism for androgen deprivation therapy failure in prostate cancer. Cancer Res. 1997;57(2):314–9.

    CAS  PubMed  Google Scholar 

  77. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447–54. https://doi.org/10.1158/0008-5472.CAN-08-0249.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Zhu H, Garcia JA. Targeting the adrenal gland in castration-resistant prostate cancer: a case for orteronel, a selective CYP-17 17,20-lyase inhibitor. Curr Oncol Rep. 2013;15(2):105–12. https://doi.org/10.1007/s11912-013-0300-1.

    Article  CAS  PubMed  Google Scholar 

  79. Heemers HV, Mohler JL. Revisiting nomenclature for the description of prostate cancer androgen-responsiveness. Am J Clin Exp Urol. 2014;2(2):121–6.

    PubMed  PubMed Central  Google Scholar 

  80. Gottlieb B, Beitel LK, Nadarajah A, et al. The androgen receptor gene mutations database: 2012 update. Hum Mutat. 2012;33(5):887–94. https://doi.org/10.1002/humu.22046.

    Article  CAS  PubMed  Google Scholar 

  81. Taplin ME, Bubley GJ, Shuster TD, et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med. 1995;332(21):1393–8. https://doi.org/10.1056/NEJM199505253322101.

    Article  CAS  PubMed  Google Scholar 

  82. Yoshida T, Kinoshita H, Segawa T, et al. Antiandrogen bicalutamide promotes tumor growth in a novel androgen-dependent prostate cancer xenograft model derived from a bicalutamide-treated patient. Cancer Res. 2005;65(21):9611–6. https://doi.org/10.1158/0008-5472.CAN-05-0817.

    Article  CAS  PubMed  Google Scholar 

  83. Zhao XY, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med. 2000;6(6):703–6. https://doi.org/10.1038/76287.

    Article  CAS  PubMed  Google Scholar 

  84. Hara T, Miyazaki J, Araki H, et al. Novel mutations of androgen receptor: a possible mechanism of bicalutamide withdrawal syndrome. Cancer Res. 2003;63(1):149–53.

    CAS  PubMed  Google Scholar 

  85. Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov. 2013;3(9):1020–9. https://doi.org/10.1158/2159-8290.CD-13-0226.

    Article  CAS  PubMed  Google Scholar 

  86. Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov. 2013;3(9):1030–43. https://doi.org/10.1158/2159-8290.CD-13-0142.

    Article  CAS  PubMed  Google Scholar 

  87. Balbas MD, Evans MJ, Hosfield DJ, et al. Overcoming mutation-based resistance to antiandrogens with rational drug design. elife. 2013;2:e00499. https://doi.org/10.7554/eLife.00499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van de Wijngaart DJ, Molier M, Lusher SJ, et al. Systematic structure-function analysis of androgen receptor Leu701 mutants explains the properties of the prostate cancer mutant L701H. J Biol Chem. 2010;285(7):5097–105. https://doi.org/10.1074/jbc.M109.039958.

    Article  CAS  PubMed  Google Scholar 

  89. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181–6. https://doi.org/10.1093/nar/22.15.3181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tut TG, Ghadessy FJ, Trifiro MA, et al. Long polyglutamine tracts in the androgen receptor are associated with reduced trans-activation, impaired sperm production, and male infertility. J Clin Endocrinol Metab. 1997;82(11):3777–82. https://doi.org/10.1210/jcem.82.11.4385.

    Article  CAS  PubMed  Google Scholar 

  91. Price DK, Chau CH, Till C, et al. Androgen receptor CAG repeat length and association with prostate cancer risk: results from the prostate cancer prevention trial. J Urol. 2010;184(6):2297–302. https://doi.org/10.1016/j.juro.2010.08.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lu C, Brown LC, Antonarakis ES, et al. Androgen receptor variant-driven prostate cancer II: advances in laboratory investigations. Prostate Cancer Prostatic Dis. 2020;23(3):381–97. https://doi.org/10.1038/s41391-020-0217-3.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Guo Z, Yang X, Sun F, et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009;69(6):2305–13. https://doi.org/10.1158/0008-5472.CAN-08-3795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hu R, Dunn TA, Wei S, et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009;69(1):16–22. https://doi.org/10.1158/0008-5472.CAN-08-2764.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen receptor splice Variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line Abiraterone and enzalutamide. J Clin Oncol. 2017;35(19):2149–56. https://doi.org/10.1200/JCO.2016.70.1961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014;371(11):1028–38. https://doi.org/10.1056/NEJMoa1315815.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hornberg E, Ylitalo EB, Crnalic S, et al. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One. 2011;6(4):e19059. https://doi.org/10.1371/journal.pone.0019059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Brown LC, Lu C, Antonarakis ES, et al. Androgen receptor variant-driven prostate cancer II: advances in clinical investigation. Prostate Cancer Prostatic Dis. 2020;23(3):367–80. https://doi.org/10.1038/s41391-020-0215-5.

    Article  CAS  PubMed  Google Scholar 

  99. Liu LL, Xie N, Sun S, et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene. 2014;33(24):3140–50. https://doi.org/10.1038/onc.2013.284.

    Article  CAS  PubMed  Google Scholar 

  100. Yu Z, Chen S, Sowalsky AG, et al. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 2014;20(6):1590–600. https://doi.org/10.1158/1078-0432.CCR-13-1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Antonarakis ES, Lu C, Luber B, et al. Androgen receptor splice variant 7 and efficacy of Taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol. 2015;1(5):582–91. https://doi.org/10.1001/jamaoncol.2015.1341.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Nakazawa M, Lu C, Chen Y, et al. Serial blood-based analysis of AR-V7 in men with advanced prostate cancer. Ann Oncol. 2015;26(9):1859–65. https://doi.org/10.1093/annonc/mdv282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mostaghel EA, Marck BT, Plymate SR, et al. Resistance to CYP17A1 inhibition with abiraterone in castration-resistant prostate cancer: induction of steroidogenesis and androgen receptor splice variants. Clin Cancer Res. 2011;17(18):5913–25. https://doi.org/10.1158/1078-0432.CCR-11-0728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Xu D, Zhan Y, Qi Y, et al. Androgen receptor splice variants Dimerize to Transactivate target genes. Cancer Res. 2015;75(17):3663–71. https://doi.org/10.1158/0008-5472.CAN-15-0381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Hu R, Lu C, Mostaghel EA, et al. Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res. 2012;72(14):3457–62. https://doi.org/10.1158/0008-5472.CAN-11-3892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Krause WC, Shafi AA, Nakka M, et al. Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol. 2014;54:49–59. https://doi.org/10.1016/j.biocel.2014.06.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen Z, Wu D, Thomas-Ahner JM, et al. Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13. Proc Natl Acad Sci U S A. 2018;115(26):6810–5. https://doi.org/10.1073/pnas.1718811115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cai L, Tsai YH, Wang P, et al. ZFX mediates non-canonical oncogenic functions of the androgen receptor splice variant 7 in castrate-resistant prostate cancer. Mol Cell. 2018;72(2):341–354 e346. https://doi.org/10.1016/j.molcel.2018.08.029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Cato L, de Tribolet-Hardy J, Lee I, et al. ARv7 represses tumor-suppressor genes in castration-resistant prostate cancer. Cancer Cell. 2019;35(3):401–413 e406. https://doi.org/10.1016/j.ccell.2019.01.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ito Y, Sadar MD. Enzalutamide and blocking androgen receptor in advanced prostate cancer: lessons learnt from the history of drug development of antiandrogens. Res Rep Urol. 2018;10:23–32. https://doi.org/10.2147/RRU.S157116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sadar MD. Small molecule inhibitors targeting the “achilles’ heel” of androgen receptor activity. Cancer Res. 2011;71(4):1208–13. https://doi.org/10.1158/0008-5472.CAN_10-3398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sadar MD. Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer. World J Urol. 2012;30(3):311–8. https://doi.org/10.1007/s00345-011-0745-5.

    Article  CAS  PubMed  Google Scholar 

  113. Yuan X, Cai C, Chen S, et al. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene. 2014;33(22):2815–25. https://doi.org/10.1038/onc.2013.235.

    Article  CAS  PubMed  Google Scholar 

  114. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–90. https://doi.org/10.1126/science.1168175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97. https://doi.org/10.1056/NEJMoa1207506.

    Article  CAS  PubMed  Google Scholar 

  116. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33. https://doi.org/10.1056/NEJMoa1405095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2018;378(26):2465–74. https://doi.org/10.1056/NEJMoa1800536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. 2012;72(6):1494–503. https://doi.org/10.1158/0008-5472.CAN-11-3948.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408–18. https://doi.org/10.1056/NEJMoa1715546.

    Article  CAS  PubMed  Google Scholar 

  120. Moilanen AM, Riikonen R, Oksala R, et al. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies. Sci Rep. 2015;5:12007. https://doi.org/10.1038/srep12007.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Borgmann H, Lallous N, Ozistanbullu D, et al. Moving towards precision urologic oncology: targeting enzalutamide-resistant prostate cancer and mutated forms of the androgen receptor using the novel inhibitor Darolutamide (ODM-201). Eur Urol. 2018;73(1):4–8. https://doi.org/10.1016/j.eururo.2017.08.012.

    Article  PubMed  Google Scholar 

  122. Zurth C, Sandman S, Trummel D, et al. Higher blood–brain barrier penetration of [14C]apalutamide and [14C]enzalutamide compared to [14C]darolutamide in rats using whole-body autoradiography. J Clin Oncol. 2019;37(157_suppl):156. https://doi.org/10.1200/JCO.2019.37.7_suppl.156.

    Article  Google Scholar 

  123. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235–46. https://doi.org/10.1056/NEJMoa1815671.

    Article  CAS  PubMed  Google Scholar 

  124. Bryce A, Ryan CJ. Development and clinical utility of abiraterone acetate as an androgen synthesis inhibitor. Clin Pharmacol Ther. 2012;91(1):101–8. https://doi.org/10.1038/clpt.2011.275.

    Article  CAS  PubMed  Google Scholar 

  125. Suzman DL, Antonarakis ES. Castration-resistant prostate cancer: latest evidence and therapeutic implications. Ther Adv Med Oncol. 2014;6(4):167–79. https://doi.org/10.1177/1758834014529176.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Cai C, Chen S, Ng P, et al. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors. Cancer Res. 2011;71(20):6503–13. https://doi.org/10.1158/0008-5472.CAN-11-0532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Andersen RJ, Mawji NR, Wang J, et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell. 2010;17(6):535–46. https://doi.org/10.1016/j.ccr.2010.04.027.

    Article  CAS  PubMed  Google Scholar 

  128. Myung JK, Banuelos CA, Fernandez JG, et al. An androgen receptor N-terminal domain antagonist for treating prostate cancer. J Clin Invest. 2013;123(7):2948–60. https://doi.org/10.1172/JCI66398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yang YC, Banuelos CA, Mawji NR, et al. Targeting androgen receptor activation function-1 with EPI to overcome resistance mechanisms in castration-resistant prostate cancer. Clin Cancer Res. 2016;22(17):4466–77. https://doi.org/10.1158/1078-0432.CCR-15-2901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. De Mol E, Fenwick RB, Phang CT, et al. EPI-001, A compound active against castration-resistant prostate cancer, targets transactivation unit 5 of the androgen receptor. ACS Chem Biol. 2016;11(9):2499–505. https://doi.org/10.1021/acschembio.6b00182.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Obst JK, Wang J, Jian K, et al. Revealing metabolic liabilities of Ralaniten to enhance novel androgen receptor targeted therapies. ACS Pharmacol Transl Sci. 2019;2(6):453–67. https://doi.org/10.1021/acsptsci.9b00065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Keating NL, O'Malley AJ, Freedland SJ, et al. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2010;102(1):39–46. https://doi.org/10.1093/jnci/djp404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Saigal CS, Gore JL, Krupski TL, et al. Androgen deprivation therapy increases cardiovascular morbidity in men with prostate cancer. Cancer. 2007;110(7):1493–500. https://doi.org/10.1002/cncr.22933.

    Article  CAS  PubMed  Google Scholar 

  134. Seruga B, Tannock IF. Intermittent androgen blockade should be regarded as standard therapy in prostate cancer. Nat Clin Pract Oncol. 2008;5(10):574–6. https://doi.org/10.1038/ncponc1180.

    Article  CAS  PubMed  Google Scholar 

  135. Denmeade SR, Isaacs JT. Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer. Prostate. 2010;70(14):1600–7. https://doi.org/10.1002/pros.21196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Markowski MC, Wang H, Sullivan R, et al. A multicohort open-label phase II trial of bipolar androgen therapy in men with metastatic castration-resistant prostate cancer (RESTORE): a comparison of post-abiraterone versus post-enzalutamide cohorts. Eur Urol. 2020; https://doi.org/10.1016/j.eururo.2020.06.042.

  137. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–42. https://doi.org/10.1016/j.mce.2017.06.013.

    Article  CAS  PubMed  Google Scholar 

  138. Wilson JD, Griffin JE, Russell DW. Steroid 5 alpha-reductase 2 deficiency. Endocr Rev. 1993;14(5):577–93. https://doi.org/10.1210/edrv-14-5-577.

    Article  CAS  PubMed  Google Scholar 

  139. Hughes IA, Houk C, Ahmed SF, et al. Consensus statement on management of intersex disorders. Arch Dis Child. 2006;91(7):554–63. https://doi.org/10.1136/adc.2006.098319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Morris JM. The syndrome of testicular feminization in male pseudohermaphrodites. Am J Obstet Gynecol. 1953;65(6):1192–211. https://doi.org/10.1016/0002-9378(53)90359-7.

    Article  CAS  PubMed  Google Scholar 

  141. Hughes IA, Davies JD, Bunch TI, et al. Androgen insensitivity syndrome. Lancet. 2012;380(9851):1419–28. https://doi.org/10.1016/S0140-6736(12)60071-3.

    Article  CAS  PubMed  Google Scholar 

  142. Hutson JM, Southwell BR, Li R, et al. The regulation of testicular descent and the effects of cryptorchidism. Endocr Rev. 2013;34(5):725–52. https://doi.org/10.1210/er.2012-1089.

    Article  CAS  PubMed  Google Scholar 

  143. Boehmer AL, Brinkmann O, Bruggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome. J Clin Endocrinol Metab. 2001;86(9):4151–60. https://doi.org/10.1210/jcem.86.9.7825.

    Article  CAS  PubMed  Google Scholar 

  144. Jagiello G, Atwell J. Prevalence of testicular feminisation. Lancet. 1962;279(7224):329. https://doi.org/10.1016/S0140-6736(62)91289-8.

    Article  Google Scholar 

  145. Oakes MB, Eyvazzadeh AD, Quint E, et al. Complete androgen insensitivity syndrome--a review. J Pediatr Adolesc Gynecol. 2008;21(6):305–10. https://doi.org/10.1016/j.jpag.2007.09.006.

    Article  PubMed  Google Scholar 

  146. Ahmed SF, Khwaja O, Hughes IA. The role of a clinical score in the assessment of ambiguous genitalia. BJU Int. 2000;85(1):120–4. https://doi.org/10.1046/j.1464-410x.2000.00354.x.

    Article  CAS  PubMed  Google Scholar 

  147. Wiesemann C. Ethical guidelines for the clinical management of intersex. Sex Dev. 2010;4(4–5):300–3. https://doi.org/10.1159/000316232.

    Article  CAS  PubMed  Google Scholar 

  148. Gottlieb B, Lombroso R, Beitel LK, et al. Molecular pathology of the androgen receptor in male (in)fertility. Reprod Biomed Online. 2005;10(1):42–8. https://doi.org/10.1016/s1472-6483(10)60802-4.

    Article  CAS  PubMed  Google Scholar 

  149. Pinsky L, Kaufman M, Killinger DW. Impaired spermatogenesis is not an obligate expression of receptor-defective androgen resistance. Am J Med Genet. 1989;32(1):100–4. https://doi.org/10.1002/ajmg.1320320121.

    Article  CAS  PubMed  Google Scholar 

  150. Lund A, Juvonen V, Lahdetie J, et al. A novel sequence variation in the transactivation regulating domain of the androgen receptor in two infertile Finnish men. Fertil Steril. 2003;79(Suppl 3):1647–8. https://doi.org/10.1016/s0015-0282(03)00256-5.

    Article  PubMed  Google Scholar 

  151. Hiort O, Sinnecker GH, Holterhus PM, et al. Inherited and de novo androgen receptor gene mutations: investigation of single-case families. J Pediatr. 1998;132(6):939–43. https://doi.org/10.1016/s0022-3476(98)70387-7.

    Article  CAS  PubMed  Google Scholar 

  152. Adachi M, Takayanagi R, Tomura A, et al. Androgen-insensitivity syndrome as a possible coactivator disease. N Engl J Med. 2000;343(12):856–62. https://doi.org/10.1056/NEJM200009213431205.

    Article  CAS  PubMed  Google Scholar 

  153. Mongan NP, Tadokoro-Cuccaro R, Bunch T, et al. Androgen insensitivity syndrome. Best Pract Res Clin Endocrinol Metab. 2015;29(4):569–80. https://doi.org/10.1016/j.beem.2015.04.005.

    Article  CAS  PubMed  Google Scholar 

  154. Nadal M, Prekovic S, Gallastegui N, et al. Structure of the homodimeric androgen receptor ligand-binding domain. Nat Commun. 2017;8:14388. https://doi.org/10.1038/ncomms14388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Topcu V, Ilgin-Ruhi H, Siklar Z, et al. Investigation of androgen receptor gene mutations in a series of 21 patients with 46,XY disorders of sex development. J Pediatr Endocrinol Metab. 2015;28(11–12):1257–63. https://doi.org/10.1515/jpem-2014-0500.

    Article  CAS  PubMed  Google Scholar 

  156. Marcelli M, Zoppi S, Grino PB, et al. A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance. J Clin Invest. 1991;87(3):1123–6. https://doi.org/10.1172/JCI115076.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Mowszowicz I, Lee HJ, Chen HT, et al. A point mutation in the second zinc finger of the DNA-binding domain of the androgen receptor gene causes complete androgen insensitivity in two siblings with receptor-positive androgen resistance. Mol Endocrinol. 1993;7(7):861–9. https://doi.org/10.1210/mend.7.7.8413310.

    Article  CAS  PubMed  Google Scholar 

  158. Sharma V, Singh R, Thangaraj K, et al. A novel Arg615Ser mutation of androgen receptor DNA-binding domain in three 46,XY sisters with complete androgen insensitivity syndrome and bilateral inguinal hernia. Fertil Steril. 2011;95(2):804 e819–821. https://doi.org/10.1016/j.fertnstert.2010.08.015.

    Article  CAS  Google Scholar 

  159. Zhou L, Wang CH. A novel arg616Cys mutation in the DNA-binding domain of complete androgen insensitivity syndrome in a Chinese family. Chin Med J. 2013;126(21):4192–3.

    PubMed  Google Scholar 

  160. Lek N, Miles H, Bunch T, et al. Low frequency of androgen receptor gene mutations in 46 XY DSD, and fetal growth restriction. Arch Dis Child. 2014;99(4):358–61. https://doi.org/10.1136/archdischild-2013-305338.

    Article  PubMed  Google Scholar 

  161. Deeb A, Mason C, Lee YS, et al. Correlation between genotype, phenotype and sex of rearing in 111 patients with partial androgen insensitivity syndrome. Clin Endocrinol. 2005;63(1):56–62. https://doi.org/10.1111/j.1365-2265.2005.02298.x.

    Article  CAS  Google Scholar 

  162. Radmayr C, Culig Z, Hobisch A, et al. Analysis of a mutant androgen receptor offers a treatment modality in a patient with partial androgen insensitivity syndrome. Eur Urol. 1998;33(2):222–6. https://doi.org/10.1159/000019540.

    Article  CAS  PubMed  Google Scholar 

  163. Batch JA, Davies HR, Evans BA, et al. Phenotypic variation and detection of carrier status in the partial androgen insensitivity syndrome. Arch Dis Child. 1993;68(4):453–7. https://doi.org/10.1136/adc.68.4.453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Mendonca BB, Domenice S, Arnhold IJ, et al. 46,XY disorders of sex development (DSD). Clin Endocrinol. 2009;70(2):173–87. https://doi.org/10.1111/j.1365-2265.2008.03392.x.

    Article  CAS  Google Scholar 

  165. Mendonca BB, Gomes NL, Costa EM, et al. 46,XY disorder of sex development (DSD) due to 17beta-hydroxysteroid dehydrogenase type 3 deficiency. J Steroid Biochem Mol Biol. 2017;165(Pt A):79–85. https://doi.org/10.1016/j.jsbmb.2016.05.002.

    Article  CAS  Google Scholar 

  166. Tadokoro-Cuccaro R, Davies J, Mongan NP, et al. Promoter-dependent activity on androgen receptor N-terminal domain mutations in androgen insensitivity syndrome. Sex Dev. 2014;8(6):339–49. https://doi.org/10.1159/000369266.

    Article  CAS  PubMed  Google Scholar 

  167. Wang Q, Ghadessy FJ, Yong EL. Analysis of the transactivation domain of the androgen receptor in patients with male infertility. Clin Genet. 1998;54(3):185–92. https://doi.org/10.1111/j.1399-0004.1998.tb04282.x.

    Article  CAS  PubMed  Google Scholar 

  168. Zuccarello D, Ferlin A, Vinanzi C, et al. Detailed functional studies on androgen receptor mild mutations demonstrate their association with male infertility. Clin Endocrinol. 2008;68(4):580–8. https://doi.org/10.1111/j.1365-2265.2007.03069.x.

    Article  CAS  Google Scholar 

  169. Audi L, Fernandez-Cancio M, Carrascosa A, et al. Novel (60%) and recurrent (40%) androgen receptor gene mutations in a series of 59 patients with a 46,XY disorder of sex development. J Clin Endocrinol Metab. 2010;95(4):1876–88. https://doi.org/10.1210/jc.2009-2146.

    Article  CAS  PubMed  Google Scholar 

  170. Hiort O, Holterhus PM, Horter T, et al. Significance of mutations in the androgen receptor gene in males with idiopathic infertility. J Clin Endocrinol Metab. 2000;85(8):2810–5. https://doi.org/10.1210/jcem.85.8.6713.

    Article  CAS  PubMed  Google Scholar 

  171. Lagarde WH, Blackwelder AJ, Minges JT, et al. Androgen receptor exon 1 mutation causes androgen insensitivity by creating phosphorylation site and inhibiting melanoma antigen-A11 activation of NH2- and carboxyl-terminal interaction-dependent transactivation. J Biol Chem. 2012;287(14):10905–15. https://doi.org/10.1074/jbc.M111.336081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Giwercman YL, Xu C, Arver S, et al. No association between the androgen receptor gene CAG repeat and impaired sperm production in Swedish men. Clin Genet. 1998;54(5):435–6.

    CAS  PubMed  Google Scholar 

  173. Hawkins MM, Barratt CL, Sutcliffe AG, et al. Male infertility and increased risk of diseases in future generations. Lancet. 1999;354(9193):1906–7. https://doi.org/10.1016/s0140-6736(05)76874-4.

    Article  CAS  PubMed  Google Scholar 

  174. Muroya K, Sasagawa I, Suzuki Y, et al. Hypospadias and the androgen receptor gene: mutation screening and CAG repeat length analysis. Mol Hum Reprod. 2001;7(5):409–13. https://doi.org/10.1093/molehr/7.5.409.

    Article  CAS  PubMed  Google Scholar 

  175. Manuel M, Katayama PK, Jones HW Jr. The age of occurrence of gonadal tumors in intersex patients with a Y chromosome. Am J Obstet Gynecol. 1976;124(3):293–300. https://doi.org/10.1016/0002-9378(76)90160-5.

    Article  CAS  PubMed  Google Scholar 

  176. Grino PB, Isidro-Gutierrez RF, Griffin JE, et al. Androgen resistance associated with a qualitative abnormality of the androgen receptor and responsive to high dose androgen therapy. J Clin Endocrinol Metab. 1989;68(3):578–84. https://doi.org/10.1210/jcem-68-3-578.

    Article  CAS  PubMed  Google Scholar 

  177. Weidemann W, Peters B, Romalo G, et al. Response to androgen treatment in a patient with partial androgen insensitivity and a mutation in the deoxyribonucleic acid-binding domain of the androgen receptor. J Clin Endocrinol Metab. 1998;83(4):1173–6. https://doi.org/10.1210/jcem.83.4.4704.

    Article  CAS  PubMed  Google Scholar 

  178. Zitzmann M. Pharmacogenetics of testosterone replacement therapy. Pharmacogenomics. 2009;10(8):1341–9. https://doi.org/10.2217/pgs.09.58.

    Article  CAS  PubMed  Google Scholar 

  179. Stein IF, Leventhal ML. Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol. 1935;29(2):181–91.

    Article  Google Scholar 

  180. Conway G, Dewailly D, Diamanti-Kandarakis E, et al. The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. Eur J Endocrinol. 2014;171(4):P1–29. https://doi.org/10.1530/EJE-14-0253.

    Article  CAS  PubMed  Google Scholar 

  181. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270–84. https://doi.org/10.1038/nrendo.2018.24.

    Article  PubMed  Google Scholar 

  182. Rotterdam EA-SPCWG. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25. https://doi.org/10.1016/j.fertnstert.2003.10.004.

    Article  Google Scholar 

  183. Keefe CC, Goldman MM, Zhang K, et al. Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. PLoS One. 2014;9(4):e93805. https://doi.org/10.1371/journal.pone.0093805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Livadas S, Pappas C, Karachalios A, et al. Prevalence and impact of hyperandrogenemia in 1,218 women with polycystic ovary syndrome. Endocrine. 2014;47(2):631–8. https://doi.org/10.1007/s12020-014-0200-7.

    Article  CAS  PubMed  Google Scholar 

  185. Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Med Sci (Basel). 2019;7(9) https://doi.org/10.3390/medsci7090089.

  186. Boyle JA, Teede HJ. PCOS: refining diagnostic features in PCOS to optimize health outcomes. Nat Rev Endocrinol. 2016;12(11):630–1. https://doi.org/10.1038/nrendo.2016.157.

    Article  CAS  PubMed  Google Scholar 

  187. Dumesic DA, Akopians AL, Madrigal VK, et al. Hyperandrogenism accompanies increased intra-abdominal fat storage in normal weight polycystic ovary syndrome women. J Clin Endocrinol Metab. 2016;101(11):4178–88. https://doi.org/10.1210/jc.2016-2586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Hu YC, Wang PH, Yeh S, et al. Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc Natl Acad Sci U S A. 2004;101(31):11209–14. https://doi.org/10.1073/pnas.0404372101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Shiina H, Matsumoto T, Sato T, et al. Premature ovarian failure in androgen receptor-deficient mice. Proc Natl Acad Sci U S A. 2006;103(1):224–9. https://doi.org/10.1073/pnas.0506736102.

    Article  CAS  PubMed  Google Scholar 

  190. Manneras L, Cajander S, Holmang A, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology. 2007;148(8):3781–91. https://doi.org/10.1210/en.2007-0168.

    Article  CAS  PubMed  Google Scholar 

  191. van Houten EL, Kramer P, McLuskey A, et al. Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology. 2012;153(6):2861–9. https://doi.org/10.1210/en.2011-1754.

    Article  CAS  PubMed  Google Scholar 

  192. Caldwell AS, Eid S, Kay CR, et al. Haplosufficient genomic androgen receptor signaling is adequate to protect female mice from induction of polycystic ovary syndrome features by prenatal hyperandrogenization. Endocrinology. 2015;156(4):1441–52. https://doi.org/10.1210/en.2014-1887.

    Article  CAS  PubMed  Google Scholar 

  193. Caldwell ASL, Edwards MC, Desai R, et al. Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2017;114(16):E3334–43. https://doi.org/10.1073/pnas.1616467114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Cox MJ, Edwards MC, Rodriguez Paris V, et al. Androgen action in adipose tissue and the brain are key mediators in the development of PCOS traits in a mouse model. Endocrinology. 2020;161(7) https://doi.org/10.1210/endocr/bqaa061.

  195. Borgbo T, Macek M Sr, Chrudimska J, et al. Size matters: associations between the androgen receptor CAG repeat length and the intrafollicular hormone milieu. Mol Cell Endocrinol. 2016;419:12–7. https://doi.org/10.1016/j.mce.2015.09.015.

    Article  CAS  PubMed  Google Scholar 

  196. Hickey T, Chandy A, Norman RJ. The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome. J Clin Endocrinol Metab. 2002;87(1):161–5. https://doi.org/10.1210/jcem.87.1.8137.

    Article  CAS  PubMed  Google Scholar 

  197. Peng CY, Xie HJ, Guo ZF, et al. The association between androgen receptor gene CAG polymorphism and polycystic ovary syndrome: a case-control study and meta-analysis. J Assist Reprod Genet. 2014;31(9):1211–9. https://doi.org/10.1007/s10815-014-0286-0.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Skrgatic L, Baldani DP, Cerne JZ, et al. CAG repeat polymorphism in androgen receptor gene is not directly associated with polycystic ovary syndrome but influences serum testosterone levels. J Steroid Biochem Mol Biol. 2012;128(3–5):107–12. https://doi.org/10.1016/j.jsbmb.2011.11.006.

    Article  CAS  PubMed  Google Scholar 

  199. Wang F, Pan J, Liu Y, et al. Alternative splicing of the androgen receptor in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2015;112(15):4743–8. https://doi.org/10.1073/pnas.1418216112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Liu Y, Wang Y, Wang F, et al. Mechanism underlying the retarded nuclear translocation of androgen receptor splice variants. Sci China Life Sci. 2019;62(2):257–67. https://doi.org/10.1007/s11427-018-9379-x.

    Article  CAS  PubMed  Google Scholar 

  201. McEwan IJ, McGuinness D, Hay CW, et al. Identification of androgen receptor phosphorylation in the primate ovary in vivo. Reproduction. 2010;140(1):93–104. https://doi.org/10.1530/REP-10-0140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Calaf J, Lopez E, Millet A, et al. Long-term efficacy and tolerability of flutamide combined with oral contraception in moderate to severe hirsutism: a 12-month, double-blind, parallel clinical trial. J Clin Endocrinol Metab. 2007;92(9):3446–52. https://doi.org/10.1210/jc.2006-2798.

    Article  CAS  PubMed  Google Scholar 

  203. De Leo V, Lanzetta D, D'Antona D, et al. Hormonal effects of flutamide in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(1):99–102. https://doi.org/10.1210/jcem.83.1.4500.

    Article  PubMed  Google Scholar 

  204. Diamanti-Kandarakis E, Mitrakou A, Raptis S, et al. The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1998;83(8):2699–705. https://doi.org/10.1210/jcem.83.8.5041.

    Article  CAS  PubMed  Google Scholar 

  205. Moghetti P, Tosi F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab. 1996;81(3):952–60. https://doi.org/10.1210/jcem.81.3.8772557.

    Article  CAS  PubMed  Google Scholar 

  206. Paradisi R, Fabbri R, Battaglia C, et al. Ovulatory effects of flutamide in the polycystic ovary syndrome. Gynecol Endocrinol. 2013;29(4):391–5. https://doi.org/10.3109/09513590.2012.754876.

    Article  CAS  PubMed  Google Scholar 

  207. Zulian E, Sartorato P, Benedini S, et al. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile. J Endocrinol Investig. 2005;28(1):49–53. https://doi.org/10.1007/BF03345529.

    Article  CAS  Google Scholar 

  208. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  209. Fioretti FM, Sita-Lumsden A, Bevan CL, et al. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol. 2014;52(3):R257–65. https://doi.org/10.1530/JME-14-0030.

    Article  CAS  PubMed  Google Scholar 

  210. Asano Y, Kashiwagi S, Goto W, et al. Expression and clinical significance of androgen receptor in triple-negative breast cancer. Cancers (Basel). 2017;9(1) https://doi.org/10.3390/cancers9010004.

  211. Prat A, Adamo B, Cheang MC, et al. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist. 2013;18(2):123–33. https://doi.org/10.1634/theoncologist.2012-0397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Anestis A, Karamouzis MV, Dalagiorgou G, et al. Is androgen receptor targeting an emerging treatment strategy for triple negative breast cancer? Cancer Treat Rev. 2015;41(6):547–53. https://doi.org/10.1016/j.ctrv.2015.04.009.

    Article  CAS  PubMed  Google Scholar 

  213. Rahim B, O'Regan R. AR signaling in breast cancer. Cancers (Basel). 2017;9(3) https://doi.org/10.3390/cancers9030021.

  214. Lehmann BD, Bauer JA, Chen X, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67. https://doi.org/10.1172/JCI45014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Hickey TE, Robinson JL, Carroll JS, et al. Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol. 2012;26(8):1252–67. https://doi.org/10.1210/me.2012-1107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. McNamara KM, Moore NL, Hickey TE, et al. Complexities of androgen receptor signalling in breast cancer. Endocr Relat Cancer. 2014;21(4):T161–81. https://doi.org/10.1530/ERC-14-0243.

    Article  CAS  PubMed  Google Scholar 

  217. Narayanan R, Dalton JT. Androgen receptor: a complex therapeutic target for breast cancer. Cancers (Basel). 2016;8(12) https://doi.org/10.3390/cancers8120108.

  218. Yeh S, Hu YC, Wang PH, et al. Abnormal mammary gland development and growth retardation in female mice and MCF7 breast cancer cells lacking androgen receptor. J Exp Med. 2003;198(12):1899–908. https://doi.org/10.1084/jem.20031233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Bleach R, McIlroy M. The divergent function of androgen receptor in breast cancer; analysis of steroid mediators and tumor intracrinology. Front Endocrinol (Lausanne). 2018;9:594. https://doi.org/10.3389/fendo.2018.00594.

    Article  Google Scholar 

  220. Christopoulos PF, Vlachogiannis NI, Vogkou CT, et al. The role of the androgen receptor signaling in breast malignancies. Anticancer Res. 2017;37(12):6533–40. https://doi.org/10.21873/anticanres.12109.

    Article  CAS  Google Scholar 

  221. Giovannelli P, Di Donato M, Galasso G, et al. The androgen receptor in breast cancer. Front Endocrinol (Lausanne). 2018;9:492. https://doi.org/10.3389/fendo.2018.00492.

    Article  Google Scholar 

  222. Vera-Badillo FE, Templeton AJ, de Gouveia P, et al. Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106(1):djt319. https://doi.org/10.1093/jnci/djt319.

    Article  CAS  Google Scholar 

  223. Aleskandarany MA, Abduljabbar R, Ashankyty I, et al. Prognostic significance of androgen receptor expression in invasive breast cancer: transcriptomic and protein expression analysis. Breast Cancer Res Treat. 2016;159(2):215–27. https://doi.org/10.1007/s10549-016-3934-5.

    Article  CAS  PubMed  Google Scholar 

  224. Hu R, Dawood S, Holmes MD, et al. Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res. 2011;17(7):1867–74. https://doi.org/10.1158/1078-0432.CCR-10-2021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Bronte G, Rocca A, Ravaioli S, et al. Androgen receptor in advanced breast cancer: is it useful to predict the efficacy of anti-estrogen therapy? BMC Cancer. 2018;18(1):348. https://doi.org/10.1186/s12885-018-4239-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Bronte G, Rocca A, Ravaioli S, et al. Evaluation of androgen receptor in relation to Estrogen Receptor (AR/ER) and Progesterone Receptor (AR/PgR): a new must in breast cancer? J Oncol. 2019;2019:1393505. https://doi.org/10.1155/2019/1393505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Rangel N, Rondon-Lagos M, Annaratone L, et al. The role of the AR/ER ratio in ER-positive breast cancer patients. Endocr Relat Cancer. 2018;25(3):163–72. https://doi.org/10.1530/ERC-17-0417.

    Article  CAS  PubMed  Google Scholar 

  228. D'Amato NC, Gordon MA, Babbs B, et al. Cooperative dynamics of AR and ER activity in breast cancer. Mol Cancer Res. 2016;14(11):1054–67. https://doi.org/10.1158/1541-7786.MCR-16-0167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. de Kruijff IE, Sieuwerts AM, Onstenk W, et al. Androgen receptor expression in circulating tumor cells of patients with metastatic breast cancer. Int J Cancer. 2019;145(4):1083–9. https://doi.org/10.1002/ijc.32209.

    Article  CAS  PubMed  Google Scholar 

  230. Aceto N, Bardia A, Wittner BS, et al. AR expression in breast cancer CTCs associates with bone metastases. Mol Cancer Res. 2018;16(4):720–7. https://doi.org/10.1158/1541-7786.MCR-17-0480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Chia KM, Liu J, Francis GD, et al. A feedback loop between androgen receptor and ERK signaling in estrogen receptor-negative breast cancer. Neoplasia. 2011;13(2):154–66. https://doi.org/10.1593/neo.101324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Naderi A, Hughes-Davies L. A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia. 2008;10(6):542–8. https://doi.org/10.1593/neo.08274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lehmann BD, Jovanovic B, Chen X, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6):e0157368. https://doi.org/10.1371/journal.pone.0157368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Jezequel P, Loussouarn D, Guerin-Charbonnel C, et al. Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response. Breast Cancer Res. 2015;17:43. https://doi.org/10.1186/s13058-015-0550-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Choi JE, Kang SH, Lee SJ, et al. Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer. Ann Surg Oncol. 2015;22(1):82–9. https://doi.org/10.1245/s10434-014-3984-z.

    Article  PubMed  Google Scholar 

  236. Barton VN, D'Amato NC, Gordon MA, et al. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol Cancer Ther. 2015;14(3):769–78. https://doi.org/10.1158/1535-7163.MCT-14-0926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lehmann BD, Bauer JA, Schafer JM, et al. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 2014;16(4):406. https://doi.org/10.1186/s13058-014-0406-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Thakkar A, Wang B, Picon-Ruiz M, et al. Vitamin D and androgen receptor-targeted therapy for triple-negative breast cancer. Breast Cancer Res Treat. 2016;157(1):77–90. https://doi.org/10.1007/s10549-016-3807-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Spurdle AB, Antoniou AC, Duffy DL, et al. The androgen receptor CAG repeat polymorphism and modification of breast cancer risk in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. 2005;7(2):R176–83. https://doi.org/10.1186/bcr971.

    Article  CAS  PubMed  Google Scholar 

  240. Spurdle AB, Dite GS, Chen X, et al. Androgen receptor exon 1 CAG repeat length and breast cancer in women before age forty years. J Natl Cancer Inst. 1999;91(11):961–6. https://doi.org/10.1093/jnci/91.11.961.

    Article  CAS  PubMed  Google Scholar 

  241. Giguere Y, Dewailly E, Brisson J, et al. Short polyglutamine tracts in the androgen receptor are protective against breast cancer in the general population. Cancer Res. 2001;61(15):5869–74.

    CAS  PubMed  Google Scholar 

  242. Hao Y, Montiel R, Li B, et al. Association between androgen receptor gene CAG repeat polymorphism and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;124(3):815–20. https://doi.org/10.1007/s10549-010-0907-y.

    Article  CAS  PubMed  Google Scholar 

  243. Hickey TE, Irvine CM, Dvinge H, et al. Expression of androgen receptor splice variants in clinical breast cancers. Oncotarget. 2015;6(42):44728–44. https://doi.org/10.18632/oncotarget.6296.

    Article  PubMed  PubMed Central  Google Scholar 

  244. Hu DG, Hickey TE, Irvine C, et al. Identification of androgen receptor splice variant transcripts in breast cancer cell lines and human tissues. Horm Cancer. 2014;5(2):61–71. https://doi.org/10.1007/s12672-014-0171-4.

    Article  CAS  PubMed  Google Scholar 

  245. Ni M, Chen Y, Lim E, et al. Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell. 2011;20(1):119–31. https://doi.org/10.1016/j.ccr.2011.05.026.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Traina TA, Miller K, Yardley DA, et al. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884–90. https://doi.org/10.1200/JCO.2016.71.3495.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Bonnefoi H, Grellety T, Tredan O, et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1). Ann Oncol. 2016;27(5):812–8. https://doi.org/10.1093/annonc/mdw067.

    Article  CAS  PubMed  Google Scholar 

  248. Gerratana L, Basile D, Buono G, et al. Androgen receptor in triple negative breast cancer: a potential target for the targetless subtype. Cancer Treat Rev. 2018;68:102–10. https://doi.org/10.1016/j.ctrv.2018.06.005.

    Article  CAS  PubMed  Google Scholar 

  249. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 2013;19(19):5505–12. https://doi.org/10.1158/1078-0432.CCR-12-3327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Hirayama Y, Tam T, Jian K, et al. Combination therapy with androgen receptor N-terminal domain antagonist EPI-7170 and enzalutamide yields synergistic activity in AR-V7-positive prostate cancer. Mol Oncol. 2020; https://doi.org/10.1002/1878-0261.12770.

  251. Chang C, Yeh S, Lee SO, et al. Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells. Nucl Recept Signal. 2013;11:e001. https://doi.org/10.1621/nrs.11001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Dunajska K, Milewicz A, Szymczak J, et al. Evaluation of sex hormone levels and some metabolic factors in men with coronary atherosclerosis. Aging Male. 2004;7(3):197–204. https://doi.org/10.1080/13685530400004181.

    Article  CAS  PubMed  Google Scholar 

  253. Turhan S, Tulunay C, Gulec S, et al. The association between androgen levels and premature coronary artery disease in men. Coron Artery Dis. 2007;18(3):159–62. https://doi.org/10.1097/MCA.0b013e328012a928.

    Article  PubMed  Google Scholar 

  254. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93(1):68–75. https://doi.org/10.1210/jc.2007-1792.

    Article  CAS  PubMed  Google Scholar 

  255. Hu JC, Williams SB, O'Malley AJ, et al. Androgen-deprivation therapy for nonmetastatic prostate cancer is associated with an increased risk of peripheral arterial disease and venous thromboembolism. Eur Urol. 2012;61(6):1119–28. https://doi.org/10.1016/j.eururo.2012.01.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Reckelhoff JF, Zhang H, Srivastava K, et al. Gender differences in hypertension in spontaneously hypertensive rats: role of androgens and androgen receptor. Hypertension. 1999;34(4 Pt 2):920–3. https://doi.org/10.1161/01.hyp.34.4.920.

    Article  CAS  PubMed  Google Scholar 

  257. Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population-based study. Circulation. 1988;78(3):539–45. https://doi.org/10.1161/01.cir.78.3.539.

    Article  CAS  PubMed  Google Scholar 

  258. Svartberg J, von Muhlen D, Schirmer H, et al. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study. Eur J Endocrinol. 2004;150(1):65–71. https://doi.org/10.1530/eje.0.1500065.

    Article  CAS  PubMed  Google Scholar 

  259. Svartberg J, von Muhlen D, Mathiesen E, et al. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006;259(6):576–82. https://doi.org/10.1111/j.1365-2796.2006.01637.x.

    Article  CAS  PubMed  Google Scholar 

  260. Traish AM, Abdou R, Kypreos KE. Androgen deficiency and atherosclerosis: the lipid link. Vasc Pharmacol. 2009;51(5–6):303–13. https://doi.org/10.1016/j.vph.2009.09.003.

    Article  CAS  Google Scholar 

  261. Shahani S, Braga-Basaria M, Basaria S. Androgen deprivation therapy in prostate cancer and metabolic risk for atherosclerosis. J Clin Endocrinol Metab. 2008;93(6):2042–9. https://doi.org/10.1210/jc.2007-2595.

    Article  CAS  PubMed  Google Scholar 

  262. Qiu Y, Yanase T, Hu H, et al. Dihydrotestosterone suppresses foam cell formation and attenuates atherosclerosis development. Endocrinology. 2010;151(7):3307–16. https://doi.org/10.1210/en.2009-1268.

    Article  CAS  PubMed  Google Scholar 

  263. Nakaguro M, Tada Y, Faquin WC, et al. Salivary duct carcinoma: updates in histology, cytology, molecular biology, and treatment. Cancer Cytopathol. 2020; https://doi.org/10.1002/cncy.22288.

  264. Tripathi A, Gupta S. Androgen receptor in bladder cancer: a promising therapeutic target. Asian J Urol. 2020;7(3):284–90. https://doi.org/10.1016/j.ajur.2020.05.011.

    Article  PubMed  PubMed Central  Google Scholar 

  265. Yuan P, Ge Y, Liu X, et al. The Association of androgen receptor expression with renal cell carcinoma risk: a systematic review and meta-analysis. Pathol Oncol Res. 2020;26(2):605–14. https://doi.org/10.1007/s12253-019-00650-z.

    Article  PubMed  Google Scholar 

  266. Simitsidellis I, Saunders PTK, Gibson DA. Androgens and endometrium: new insights and new targets. Mol Cell Endocrinol. 2018;465:48–60. https://doi.org/10.1016/j.mce.2017.09.022.

    Article  CAS  PubMed  Google Scholar 

  267. Kanda T, Jiang X, Yokosuka O. Androgen receptor signaling in hepatocellular carcinoma and pancreatic cancers. World J Gastroenterol. 2014;20(28):9229–36. https://doi.org/10.3748/wjg.v20.i28.9229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Schweizer MT, Yu EY. AR-signaling in human malignancies: prostate cancer and beyond. Cancers (Basel). 2017;9(1) https://doi.org/10.3390/cancers9010007.

  269. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. https://doi.org/10.3322/caac.21551.

    Article  PubMed  Google Scholar 

  270. Miyamoto H, Yang Z, Chen YT, et al. Promotion of bladder cancer development and progression by androgen receptor signals. J Natl Cancer Inst. 2007;99(7):558–68. https://doi.org/10.1093/jnci/djk113.

    Article  CAS  PubMed  Google Scholar 

  271. Juan YS, Onal B, Broadaway S, et al. Effect of castration on male rabbit lower urinary tract tissue enzymes. Mol Cell Biochem. 2007;301(1–2):227–33. https://doi.org/10.1007/s11010-007-9415-8.

    Article  CAS  PubMed  Google Scholar 

  272. Shortliffe LM, Ye Y, Behr B, et al. Testosterone changes bladder and kidney structure in juvenile male rats. J Urol. 2014;191(6):1913–9. https://doi.org/10.1016/j.juro.2014.01.012.

    Article  CAS  PubMed  Google Scholar 

  273. Li P, Chen J, Miyamoto H. Androgen receptor signaling in bladder cancer. Cancers (Basel). 2017;9(2) https://doi.org/10.3390/cancers9020020.

  274. Li Y, Zheng Y, Izumi K, et al. Androgen activates beta-catenin signaling in bladder cancer cells. Endocr Relat Cancer. 2013;20(3):293–304. https://doi.org/10.1530/ERC-12-0328.

    Article  CAS  PubMed  Google Scholar 

  275. Wu JT, Han BM, Yu SQ, et al. Androgen receptor is a potential therapeutic target for bladder cancer. Urology. 2010;75(4):820–7. https://doi.org/10.1016/j.urology.2009.10.041.

    Article  PubMed  Google Scholar 

  276. Hu C, Fang D, Xu H, et al. The androgen receptor expression and association with patient's survival in different cancers. Genomics. 2020;112(2):1926–40. https://doi.org/10.1016/j.ygeno.2019.11.005.

    Article  CAS  PubMed  Google Scholar 

  277. Langner C, Ratschek M, Rehak P, et al. Steroid hormone receptor expression in renal cell carcinoma: an immunohistochemical analysis of 182 tumors. J Urol. 2004;171(2 Pt 1):611–4. https://doi.org/10.1097/01.ju.0000108040.14303.c2.

    Article  CAS  PubMed  Google Scholar 

  278. Zhu G, Liang L, Li L, et al. The expression and evaluation of androgen receptor in human renal cell carcinoma. Urology. 2014;83(2):510 e519–524. https://doi.org/10.1016/j.urology.2013.10.022.

    Article  Google Scholar 

  279. Zhang H, Li XX, Yang Y, et al. Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross-talk in hepatocellular carcinoma. Hepatology. 2018;67(6):2271–86. https://doi.org/10.1002/hep.29715.

    Article  CAS  PubMed  Google Scholar 

  280. Ma WL, Hsu CL, Yeh CC, et al. Hepatic androgen receptor suppresses hepatocellular carcinoma metastasis through modulation of cell migration and anoikis. Hepatology. 2012;56(1):176–85. https://doi.org/10.1002/hep.25644.

    Article  CAS  PubMed  Google Scholar 

  281. Steinkamp MP, O'Mahony OA, Brogley M, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69(10):4434–42. https://doi.org/10.1158/0008-5472.CAN-08-3605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Robins DM. Androgen receptor gene polymorphisms and alterations in prostate cancer: of humanized mice and men. Mol Cell Endocrinol. 2012;352(1–2):26–33. https://doi.org/10.1016/j.mce.2011.06.003.

    Article  CAS  PubMed  Google Scholar 

  283. Nazareth LV, Stenoien DL, Bingman WE 3rd, et al. A C619Y mutation in the human androgen receptor causes inactivation and mislocalization of the receptor with concomitant sequestration of SRC-1 (steroid receptor coactivator 1). Mol Endocrinol. 1999;13(12):2065–75. https://doi.org/10.1210/mend.13.12.0382.

    Article  CAS  PubMed  Google Scholar 

  284. Marcelli M, Ittmann M, Mariani S, et al. Androgen receptor mutations in prostate cancer. Cancer Res. 2000;60(4):944–9.

    CAS  PubMed  Google Scholar 

  285. Lallous N, Volik SV, Awrey S, et al. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients. Genome Biol. 2016;17:10. https://doi.org/10.1186/s13059-015-0864-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  286. Culig Z, Hobisch A, Cronauer MV, et al. Mutant androgen receptor detected in an advanced-stage prostatic carcinoma is activated by adrenal androgens and progesterone. Mol Endocrinol. 1993;7(12):1541–50. https://doi.org/10.1210/mend.7.12.8145761.

    Article  CAS  PubMed  Google Scholar 

  287. Elo JP, Kvist L, Leinonen K, et al. Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol. J Clin Endocrinol Metab. 1995;80(12):3494–500. https://doi.org/10.1210/jcem.80.12.8530589.

    Article  CAS  PubMed  Google Scholar 

  288. Mononen N, Syrjakoski K, Matikainen M, et al. Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene. Cancer Res. 2000;60(22):6479–81.

    CAS  PubMed  Google Scholar 

  289. Bohl CE, Gao W, Miller DD, et al. Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci U S A. 2005;102(17):6201–6. https://doi.org/10.1073/pnas.0500381102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Wilding G, Chen M, Gelmann E. Aberrant response in vitro of hormone-responsive prostate cancer cells to antiandrogens. Prostate. 1989;14(2):103–15. https://doi.org/10.1002/pros.2990140204.

    Article  Google Scholar 

  291. Veldscholte J, Berrevoets CA, Ris-Stalpers C, et al. The androgen receptor in LNCaP cells contains a mutation in the ligand binding domain which affects steroid binding characteristics and response to antiandrogens. J Steroid Biochem Mol Biol. 1992;41(3–8):665–9. https://doi.org/10.1016/0960-0760(92)90401-4.

    Article  CAS  PubMed  Google Scholar 

  292. Gottlieb B, Pinsky L, Beitel LK, et al. Androgen insensitivity. Am J Med Genet. 1999;89(4):210–7. https://doi.org/10.1002/(sici)1096-8628(19991229)89:4<210::aid-ajmg5>3.0.co;2-p.

    Article  CAS  PubMed  Google Scholar 

  293. Cheikhelard A, Morel Y, Thibaud E, et al. Long-term followup and comparison between genotype and phenotype in 29 cases of complete androgen insensitivity syndrome. J Urol. 2008;180(4):1496–501. https://doi.org/10.1016/j.juro.2008.06.045.

    Article  PubMed  Google Scholar 

  294. Giwercman A, Kledal T, Schwartz M, et al. Preserved male fertility despite decreased androgen sensitivity caused by a mutation in the ligand-binding domain of the androgen receptor gene. J Clin Endocrinol Metab. 2000;85(6):2253–9. https://doi.org/10.1210/jcem.85.6.6626.

    Article  CAS  PubMed  Google Scholar 

  295. Pinsky L, Trifiro M, Kaufman M, et al. Androgen resistance due to mutation of the androgen receptor. Clin Invest Med. 1992;15(5):456–72.

    Google Scholar 

  296. Chávez B, Méndez JP, Ulloa-Aguirre A, et al. Eight novel mutations of the androgen receptor gene in patients with androgen insensitivity syndrome. J Hum Genet. 2001;46(10):560–5. https://doi.org/10.1007/s100380170021.

    Article  PubMed  Google Scholar 

  297. Hiort O, Sinnecker GH, Holterhus PM, et al. The clinical and molecular spectrum of androgen insensitivity syndromes. Am J Med Genet. 1996;63(1):218–22. https://doi.org/10.1002/(SICI)1096-8628(19960503)63:1<218::AID-AJMG38>3.0.CO;2-P.

    Article  CAS  PubMed  Google Scholar 

  298. Hannema SE, Scott IS, Hodapp J, et al. Residual activity of mutant androgen receptors explains wolffian duct development in the complete androgen insensitivity syndrome. J Clin Endocrinol Metab. 2004;89(11):5815–22. https://doi.org/10.1210/jc.2004-0709.

    Article  CAS  PubMed  Google Scholar 

  299. Bouvattier C, Carel JC, Lecointre C, et al. Postnatal changes of T, LH, and FSH in 46,XY infants with mutations in the AR gene. J Clin Endocrinol Metab. 2002;87(1):29–32. https://doi.org/10.1210/jcem.87.1.7923.

    Article  CAS  PubMed  Google Scholar 

  300. Ledig S, Jakubiczka S, Neulen J, et al. Novel and recurrent mutations in patients with androgen insensitivity syndromes. Horm Res. 2005;63(6):263–9. https://doi.org/10.1159/000086018.

    Article  CAS  PubMed  Google Scholar 

  301. Bevan CL, Brown BB, Davies HR, et al. Functional analysis of six androgen receptor mutations identified in patients with partial androgen insensitivity syndrome. Hum Mol Genet. 1996;5(2):265–73. https://doi.org/10.1093/hmg/5.2.265.

    Article  CAS  PubMed  Google Scholar 

  302. Hellmann P, Christiansen P, Johannsen TH, et al. Male patients with partial androgen insensitivity syndrome: a longitudinal follow-up of growth, reproductive hormones and the development of gynaecomastia. Arch Dis Child. 2012;97(5):403–9. https://doi.org/10.1136/archdischild-2011-300584.

    Article  PubMed  Google Scholar 

  303. Georget V, Terouanne B, Lumbroso S, et al. Trafficking of androgen receptor mutants fused to green fluorescent protein: a new investigation of partial androgen insensitivity syndrome. J Clin Endocrinol Metab. 1998;83(10):3597–603. https://doi.org/10.1210/jcem.83.10.5201.

    Article  CAS  PubMed  Google Scholar 

  304. Beitel LK, Prior L, Vasiliou DM, et al. Complete androgen insensitivity due to mutations in the probable alpha-helical segments of the DNA-binding domain in the human androgen receptor. Hum Mol Genet. 1994;3(1):21–7. https://doi.org/10.1093/hmg/3.1.21.

    Article  CAS  PubMed  Google Scholar 

  305. Lubahn DB, Joseph DR, Sullivan PM, et al. Cloning of human androgen receptor complementary DNA and localization to the X chromosome. Science. 1988;240(4850):327–30. https://doi.org/10.1126/science.3353727.

    Article  CAS  PubMed  Google Scholar 

  306. De Mol E, Szulc E, Di Sanza C, et al. Regulation of androgen receptor activity by transient interactions of its transactivation domain with general transcription regulators. Structure. 2018;26(1):145–152 e143. https://doi.org/10.1016/j.str.2017.11.007.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the US National Cancer Institute grant number 2R01 CA105304.

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Authors and Affiliations

  1. Canada’s Michael Smith Genome Sciences Centre at BC Cancer, Vancouver, BC, Canada

    Jacky K. Leung, Amy H. Tien & Marianne D. Sadar

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  1. Jacky K. Leung
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  2. Amy H. Tien
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Correspondence to Marianne D. Sadar .

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  1. School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA

    Mostafa Z. Badr

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Leung, J.K., Tien, A.H., Sadar, M.D. (2021). Androgen Receptors in the Pathology of Disease. In: Badr, M.Z. (eds) Nuclear Receptors. Springer, Cham. https://doi.org/10.1007/978-3-030-78315-0_16

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