Breast Cancer Research and Treatment

, Volume 158, Issue 3, pp 553–561 | Cite as

A novel approach to breast cancer prevention: reducing excessive ovarian androgen production in elderly women

  • Giorgio Secreto
  • Sabina Sieri
  • Claudia Agnoli
  • Sara Grioni
  • Paola Muti
  • Barnett Zumoff
  • Milena Sant
  • Elisabetta Meneghini
  • Vittorio Krogh


Minimizing endogenous estrogen production and activity in women at high risk for breast cancer is a prominent approach to prevention of the disease. A number of clinical trials have shown that the administration of selective-estrogen receptor modulators or aromatase inhibitors significantly reduces the incidence of breast cancer in healthy women. Unfortunately, these drugs often produce adverse effects on the quality of life and are, therefore, poorly accepted by many women, even those who are at high risk for breast cancer. We propose a novel alternative approach to decreasing estrogen production: suppression of ovarian synthesis of the androgen precursors of estrogens by administration of long-acting gonadotropin-releasing hormone analogs to women with ovarian stromal hyperplasia. The specific target population would be elderly postmenopausal women, at increased risk of breast cancer, and with high blood levels of testosterone, marker of ovarian hyperandrogenemia, and recognized factor of risk for breast cancer. Testosterone levels are measured at baseline to identify women at risk and during the follow-up to evaluate the effectiveness of therapy. The postmenopausal ovary is an important source of excessive androgen production which originates from the ovarian interstitial cell hyperplasia frequently present in breast cancer patients. We propose to counter the source of androgen excess in women with ovarian stromal hyperplasia, thus reducing the substrate for estrogen formation without completely inhibiting estrogen synthesis. Available evidence indicates that gonadotropin-releasing hormone analogs can be safely used for breast cancer prevention in postmenopausal women.


Breast cancer prevention Postmenopausal ovary Testosterone levels GnRH analogs Ovarian stromal hyperplasia 



Androgen receptors


Benign breast disease






Epidermal growth factor


Epidermal growth factor receptor


Human epidermal growth factor receptor 2


Estrogen receptor


Follicle stimulating hormone


Gonadotropin-releasing hormone


Luteinizing hormone




Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Cuzick J, Sestak I, Bonanni B, Costantino JP, Cummings S, DeCensi A, Dowsett M, Forbes JF, Ford L, LaCroix AZ, Mershon J, Mitlak BH, Powles T, Veronesi U, Vogel V, Wickerham DL (2013) SERM chemoprevention of breast cancer overview group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 381:1827–1834CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, McTiernan A, Robbins J, Johnson KC, Martin LW, Winquist E, Sarto GE, Garber JE, Fabian CJ, Pujol P, Maunsell E, Farmer P, Gelmon KA, Tu D, Richardson H (2011) NCIC CTG MAP.3 study investigators: exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364:2381–2391CrossRefPubMedGoogle Scholar
  3. 3.
    Cuzick J, Sestak I, Forbes JF, Dowsett M, Knox J, Cawthorn S, Saunders C, Roche N, Mansel RE, von Minckwitz G, Bonanni B, Palva T, Howell A, on behalf of the IBIS-II investigators (2014) Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomized placebo-controlled trial. Lancet 383:1041–1048CrossRefPubMedGoogle Scholar
  4. 4.
    Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, Davidson NE, Decensi A, Fabian C, Ford L, Garber J, Katapodi M, Kramer B, Morrow M, Parker B, Runowicz C, Vogel VG 3rd, Wade JL, Lippman SM (2013) Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 31:2942–2962CrossRefPubMedGoogle Scholar
  5. 5.
    Ropka ME, Keim J, Philbrick JT (2010) Patient decisions about breast cancer chemoprevention: a systematic review and meta-analysis. J Clin Oncol 28:3090–3095CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Waters EA, Cronin KA, Graubard BI, Han PK, Freedman AN (2010) Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women. Cancer Epidemiol Biomark Prev 19:443–446CrossRefGoogle Scholar
  7. 7.
    Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, Mulvihill JJ (1989) Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81:1879–1886CrossRefPubMedGoogle Scholar
  8. 8.
    Rockhill B, Spiegelman D, Byrne C, Hunter DJ, Colditz GA et al (2001) Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst 93:358–366CrossRefPubMedGoogle Scholar
  9. 9.
    Tyrer J, Duffy SW, Cuzick J (2004) A breast cancer prediction model incorporating familial and personal risk factors. Stat Med 23:1111–1130CrossRefPubMedGoogle Scholar
  10. 10.
    Meads C, Ahmed I, Riley RD (2012) A systematic review of breast cancer incidence risk prediction models with meta-analysis of their performance. Breast Cancer Res Treat 132:365–377CrossRefPubMedGoogle Scholar
  11. 11.
    Secreto G (2012) The androgen-excess theory of breast cancer. In: Secreto G, Zumoff B (eds) The androgen-excess theory of breast cancer, Research Signpost, Trivandrum, pp 47–70.
  12. 12.
    Yancik R, Wesley MN, Lynn AG, Ries LAG, Havlik RJ, Edwards BK, Yates JW (2001) Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885–892CrossRefPubMedGoogle Scholar
  13. 13.
    Anderson WF, Pfeiffer RM, Dores GM, Sherman ME (2006) Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomark Prev 15:1899–1905CrossRefGoogle Scholar
  14. 14.
    Gruber CJ, Tschugguel W, Schneeberger C, Huber JC (2002) Production and actions of estrogens. N Engl J Med 346:340–352CrossRefPubMedGoogle Scholar
  15. 15.
    Key T, Appleby P, Barnes I, Reeves G (2002) Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94:606–616CrossRefPubMedGoogle Scholar
  16. 16.
    Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE (2004) Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst 96:1856–1865CrossRefPubMedGoogle Scholar
  17. 17.
    Cummings SR, Lee JS, Lui LY, Stone K, Ljung BM, Cauleys JA (2005) Sex hormones, risk factors, and risk of estrogen receptor–positive breast cancer in older women: a long-term prospective study. Cancer Epidemiol Biomark Prev 14:1047–1051CrossRefGoogle Scholar
  18. 18.
    Secreto G (2012) Endocrine classification of postmenopausal breast cancers. In: Secreto G, Zumoff B (eds) The androgen-excess theory of breast cancer, Research Signpost, Trivandrum, pp 79–109.
  19. 19.
    Secreto G, Venturelli E, Meneghini E, Carcangiu ML, Paolini B, Agresti R, Pellitteri C, Berrino F, Gion M, Cogliati P, Saragò G, Micheli A (2012) Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers. BMC Cancer 12:599CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Secreto G, Venturelli E, Meneghini E, Greco M, Ferraris C, Gion M, Zancan M, Fabricio AS, Berrino F, Cavalleri A, Micheli A (2009) Testosterone and biological characteristics of breast cancers in postmenopausal women. Cancer Epidemiol Biomark Prev 18:2942–2948CrossRefGoogle Scholar
  21. 21.
    Secreto G, Meneghini E, Venturelli E, Cogliati P, Agresti R, Ferraris C, Gion M, Zancan M, Fabricio AS, Berrino F, Cavalleri A, Micheli A (2011) Circulating sex hormones and tumor characteristics in postmenopausal breast cancer patients. A cross-sectional study. Int J Biol Markers 26:241–246PubMedGoogle Scholar
  22. 22.
    Burger HG (2002) Androgen production in women. Fertil Steril 77(Suppl 4):S3–S5CrossRefPubMedGoogle Scholar
  23. 23.
    Kotsopoulos J, Narod SA (2012) Androgens and breast cancer. Steroids 77:1–9CrossRefPubMedGoogle Scholar
  24. 24.
    Zumoff B, Strain GW, Miller LK, Rosner W (1995) Twenty-four-hour mean plasma testosterone concentration declines with age in normal premenopausal women. J Clin Endocrinol Metab 80:1429–1430PubMedGoogle Scholar
  25. 25.
    Davison SL, Bell R, Donath S, Montalto JG, Davis SR (2005) Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 90:3847–3853CrossRefPubMedGoogle Scholar
  26. 26.
    Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL (2000) A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab 85:2832–2838PubMedGoogle Scholar
  27. 27.
    Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ (2007) Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metab 92:3040–3043CrossRefPubMedGoogle Scholar
  28. 28.
    Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Mühlen D (2000) Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: the Rancho Bernardo study. J Clin Endocrinol Metab 85:645–651PubMedGoogle Scholar
  29. 29.
    Sowers MFR, Zheng H, McConnell D, Nan B, Karvonen-Gutierrez CA, Randolph JF Jr (2009) Testosterone, sex hormone-binding globulin and free androgen index among adult women: chronological and ovarian aging. Hum Reprod 24:2276–2285CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Adashi EY (1994) The climacteric ovary as a functional gonadotropin-driven androgen-producing gland. Fertil Steril 62:20–27CrossRefPubMedGoogle Scholar
  31. 31.
    Jongen VH, Sluijmer AV, Heineman MJ (2002) The postmenopausal ovary as an androgen-producing gland; hypothesis on the etiology of endometrial cancer. Maturitas 43:77–85CrossRefPubMedGoogle Scholar
  32. 32.
    Rice BF, Savard K (1966) Steroid hormone formation in the human ovary. IV. Ovarian stromal compartment; formation of radioactive steroids from acetate-1–14C and action of gonadotropins. J Clin Endocrinol Metab 26:593–609CrossRefPubMedGoogle Scholar
  33. 33.
    Stegner HE (1989) Hormonally related non-neoplastic condition of the ovary. In: Nogales Francisco (ed) Ovarian pathology, current topics in pathology. Springer, Berlin, pp 11–39Google Scholar
  34. 34.
    Sommers SC (1952) Ovarian stromal hyperplasia in breast cancer. AMA Arch Pathol 53:160–166PubMedGoogle Scholar
  35. 35.
    Lucisano A, Russo N, Acampora MG, Fabiano A, Fattibene M, Parlati E, Maniccia E, Dell’Acqua S (1986) Ovarian and peripheral androgen and oestrogen levels in post-menopausal women: correlations with ovarian histology. Maturitas 8:57–65CrossRefPubMedGoogle Scholar
  36. 36.
    Sluijmer AV, Heineman MJ, Koudstaal J, Theunissen PH, de Jong FH, Evers JL (1998) Relationship between ovarian production of estrone, estradiol, testosterone, and androstenedione and the ovarian degree of stromal hyperplasia in postmenopausal women. Menopause 5:207–210CrossRefPubMedGoogle Scholar
  37. 37.
    Jongen VHWM, Holleman H, van der Zee AGJ, Santema JG, Heineman MJ (2003) Ovarian stromal hyperplasia and ovarian vein steroid levels in relation to endometrioid endometrial cancer. Br J Obstet Gynaecol 110:690–695CrossRefGoogle Scholar
  38. 38.
    Kotsopoulos J, Lubinski J, Lynch HT, Kim-Sing C, Neuhausen S, Demsky R, Foulkes WD, Ghadirian P, Tung N, Ainsworth P, Senter L, Karlan B, Eisen A, Eng C, Weitzel J, Gilchrist DM, Blum JL, Zakalik D, Singer C, Fallen T, Ginsburg O, Huzarski T, Sun P, Narod SA (2012) Oophorectomy after menopause and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomark Prev 21:1089–1096CrossRefGoogle Scholar
  39. 39.
    Kotsopoulos J, Shafrir AL, Rice M, Hankinson SE, Eliassen AH, Tworoger SS, Narod SA (2015) The relationship between bilateral oophorectomy and plasma hormone levels in postmenopausal women. Horm Cancer 6:54–63CrossRefPubMedGoogle Scholar
  40. 40.
    Boyd NF, Martin LJ, Yaffe MJ, Minkin S (2011) Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res 13:223CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tamimi RM, Byrne C, Colditz GA, Hankinson SE (2007) Endogenous hormone levels, mammographic density, and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 99:1178–1187CrossRefPubMedGoogle Scholar
  42. 42.
    Schoemaker MJ, Folkerd EJ, Jones ME, Rae M, Allen S, Ashworth A, Dowsett M, Swerdlow AJ (2014) Combined effects of endogenous sex hormone levels and mammographic density on postmenopausal breast cancer risk: results from the Breakthrough Generations Study. Br J Cancer 110:1898–1907CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Cuzick J, Warwick J, Pinney E, Duffy SW, Cawthorn S, Howell A, Forbes JF, Warren RM (2011) Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case-control study. J Natl Cancer Inst 103:744–752CrossRefPubMedGoogle Scholar
  44. 44.
    Secreto G, Zumoff B (2012) Role of androgen excess in the development of estrogen receptor-positive and estrogen receptor-negative breast cancer. Anticancer Res 32:3223–3228PubMedGoogle Scholar
  45. 45.
    Zhang X, Tworoger SS, Eliassen AH, Hankinson SE (2013) Postmenopausal plasma sex hormone levels and breast cancer risk over 20 years of follow-up. Breast Cancer Res Treat 137:883–892CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Endogenous Hormones and Breast Cancer Collaborative Group (2015) Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: reanalysis of eighteen prospective studies. Steroids 99:49–55CrossRefGoogle Scholar
  47. 47.
    Berrino F, Pasanisi P, Bellati C, Venturelli E, Krogh V, Mastroianni A, Berselli E, Muti P, Secreto G (2005) Serum testosterone levels and breast cancer recurrence. Int J Cancer 113:499–502CrossRefPubMedGoogle Scholar
  48. 48.
    Micheli A, Meneghini E, Secreto G, Berrino F, Venturelli E, Cavalleri A, Camerini T, Di Mauro MG, Cavadini E, De Palo G, Veronesi U, Formelli F (2007) Plasma testosterone and prognosis of postmenopausal breast cancer patients. J Clin Oncol 25:2685–2690CrossRefPubMedGoogle Scholar
  49. 49.
    Berrino F, Bellati C, Secreto G, Camerini E, Pala V, Panico S, Allegro G, Kaaks R (2001) Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol Biomark Prev 10:25–33Google Scholar
  50. 50.
    Kushnir MM, Rockwood AL, Roberts WL, Pattison EG, Bunker AM, Fitzgerald RL, Meikle AW (2006) Performance characteristics of a novel tandem mass spectrometry assay for serum testosterone. Clin Chem 52:120–128CrossRefPubMedGoogle Scholar
  51. 51.
    Rosner W, Auchus RJ, Azziz R, Sluss PM, Raff H (2007) Position statement: utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement. J Clin Endocrinol Metab 92:405–413CrossRefPubMedGoogle Scholar
  52. 52.
    Moal V, Mathieu E, Reynier P, Malthièry Y, Gallois Y (2007) Low serum testosterone assayed by liquid chromatography-tandem mass spectrometry. Comparison with five immunoassay techniques. Clin Chim Acta 386:12–19CrossRefPubMedGoogle Scholar
  53. 53.
    Ketha H, Kaur S, Grebe SK, Singh RJ (2014) Clinical applications of LC-MS sex steroid assays: evolution of methodologies in the 21st century. Curr Opin Endocrinol Diabetes Obes 21:217–226CrossRefPubMedGoogle Scholar
  54. 54.
    Plowman PN, Nicholson RI, Walker KJ (1986) Remission of postmenopausal breast cancer during treatment with the luteinising hormone releasing hormone agonist ICI 118630. Br J Cancer 54:903–909CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Crighton IL, Dowsett M, Lal A, Man A, Smith IE (1989) Use of luteinising hormone-releasing hormone agonist (leuprorelin) in advanced post-menopausal breast cancer: clinical and endocrine effects. Br J Cancer 60:644–648CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Dowsett M, Jacobs S, Aherne J, Smith IE (1992) Clinical and endocrine effects of leuprorelin acetate in pre- and postmenopausal patients with advanced breast cancer. Clin Ther 14:97–103PubMedGoogle Scholar
  57. 57.
    Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B (2002) Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: Zoladex Early Breast Cancer Research Association Study. J Clin Oncol 20:4628–4635CrossRefPubMedGoogle Scholar
  58. 58.
    International Breast Cancer Study Group (IBCSG), Castiglione-Gertsch M, O’Neill A, Price KN, Goldhirsch A, Coates AS, Colleoni M, Nasi ML, Bonetti M, Gelber RD (2003) Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 95:1833–1846CrossRefGoogle Scholar
  59. 59.
    Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K (2007) Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol 25:2509–2515CrossRefPubMedGoogle Scholar
  60. 60.
    Exemestane with ovarian suppression in premenopausal breast cancer, Pagani O, Regan MM, Francis PA (2014) Exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371:1358–1359Google Scholar
  61. 61.
    Hughes CL Jr, Wall LL, Creasman WT (1991) Reproductive hormone levels in gynecologic oncology patients undergoing surgical castration after spontaneous menopause. Gynecol Oncol 40:42–45CrossRefPubMedGoogle Scholar
  62. 62.
    Folkerd EJ, Jacobs HS, van der Spuy Z, James VH (1982) Failure of FSH to influence aromatization in human adipose tissue. Clin Endocrinol (Oxf) 16:621–625CrossRefGoogle Scholar
  63. 63.
    Simpson ER, Cleland WH, Mendelson CR (1983) Aromatization of androgens by human adipose tissue in vitro. J Steroid Biochem 19:707–713CrossRefPubMedGoogle Scholar
  64. 64.
    Zhao Y, Nichols JE, Bulun SE, Mendelson CR, Simpson ER (1995) Aromatase P450 gene expression in human adipose tissue. Role of a Jak/STAT pathway in regulation of the adipose-specific promoter. J Biol Chem 270:16449–16457CrossRefPubMedGoogle Scholar
  65. 65.
    Bulun SE, Lin Z, Imir G, Amin S, Demura M, Yilmaz B, Martin R, Utsunomiya H, Thung S, Gurates B, Tamura M, Langoi D, Deb S (2005) Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment. Pharmacol Rev 57:359–383CrossRefPubMedGoogle Scholar
  66. 66.
    Spicer DV, Ursin G, Parisky YR, Pearce JG, Shoupe D, Pike A, Pike MC (1994) Changes in mammographic densities induced by a hormonal contraceptive designed to reduce breast cancer risk. J Natl Cancer Inst 86:431–436CrossRefPubMedGoogle Scholar
  67. 67.
    Suzuki T, Miki Y, Akahira J, Moriya T, Ohuchi N, Sasano H (2008) Aromatase in human breast carcinomas a key regulator of intratumor sex steroid concentrations. Endocr J 55:455–463CrossRefPubMedGoogle Scholar
  68. 68.
    Peters AA, Buchanan G, Ricciarelli C, Bianco-Miotto T, Centenera MM, Harris JM, Jindal S, Segara D, Jia L, Moore NL, Henshall SM, Birrell SN, Coetzee GA, Sutherland RL, Butler LM, Tilley WD (2009) Androgen receptor inhibits estrogen receptor-a activity and is prognostic in breast cancer. Cancer Res 69:6131–6140CrossRefPubMedGoogle Scholar
  69. 69.
    Hickey TE, Robinson JL, Carroll JS, Tilley WD (2012) Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26:1252–1267CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    McNamara KM, Moore NL, Hickey TE, Sasano H, Tilley WD (2014) Complexities of androgen receptor signalling in breast cancer. Endocr Relat Cancer 21:T161–T181CrossRefPubMedGoogle Scholar
  71. 71.
    Massarweh S, Osborne CK, Creighton CJ, Qin L, Tsimelzon A, Huang S, Weiss H, Rimawi M, Schiff R (2008) Tamoxifen resistance in breast tumors is driven by growth factor receptor signaling with repression of classic estrogen receptor genomic function. Cancer Res 68:826–833CrossRefPubMedGoogle Scholar
  72. 72.
    De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I, Weigel NL, Herynk MH, Tsimelzon A, Lewis MT, Chamness GC, Hilsenbeck SG, Andò S, Fuqua SA (2010) Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat 121:1–11CrossRefPubMedGoogle Scholar
  73. 73.
    Rechoum Y, Rovito D, Iacopetta D, Barone I, Andò S, Weigel NL, O’Malley BW, Brown PH, Fuqua SA (2014) AR collaborates with ERα in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat 147:473–485CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Fujii R, Hanamura T, Suzuki T, Gohno T, Shibahara Y, Niwa T, Yamaguchi Y, Ohnuki K, Kakugawa Y, Hirakawa H, Ishida T, Sasano H, Ohuchi N, Hayashi S (2014) Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J Steroid Biochem Mol Biol 144:513–522CrossRefPubMedGoogle Scholar
  75. 75.
    Ciupek A, Rechoum Y, Gu G, Gelsomino L, Beyer AR, Brusco L, Covington KR, Tsimelzon A, Fuqua SA (2015) Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer. Breast Cancer Res Treat 154:225–237CrossRefPubMedGoogle Scholar
  76. 76.
    Allred DC (2010) Ductal carcinoma in situ: terminology, classification, and natural history. J Natl Cancer Inst Monogr 41:134–138CrossRefGoogle Scholar
  77. 77.
    Allred DC, Mohsin SK, Fuqua SA (2001) Histological and biological evolution of human premalignant breast disease. Endocr Relat Cancer 8(1):47–61CrossRefPubMedGoogle Scholar
  78. 78.
    Moinfar F, Okcu M, Tsybrovskyy O, Regitnig P, Lax SF, Weybora W, Ratschek M, Tavassoli FA, Denk H (2003) Androgen receptors frequently are expressed in breast carcinomas: potential relevance to new therapeutic strategies. Cancer 98:703–711CrossRefPubMedGoogle Scholar
  79. 79.
    Shibuya R, Suzuki T, Miki Y, Yoshida K, Moriya T, Ono K, Akahira J, Ishida T, Hirakawa H, Evans DB, Sasano H (2008) Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast. Endocr Relat Cancer 15:113–124CrossRefPubMedGoogle Scholar
  80. 80.
    Sasaki Y, Miki Y, Hirakawa H, Onodera Y, Takagi K, Akahira J, Honma S, Ishida T, Watanabe M, Sasano H, Suzuki T (2010) Immunolocalization of estrogen-producing and metabolizing enzymes in benign breast disease: comparison with normal breast and breast carcinoma. Cancer Sci 101:2286–2292CrossRefPubMedGoogle Scholar
  81. 81.
    Lari SA, Kuerer HM (2011) Biological markers in DCIS and risk of breast recurrence: a systematic review. J Cancer 2:232–261CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Hanley K, Wang J, Bourne P, Yang Q, Gao AC, Lyman G, Tang P (2008) Lack of expression of androgen receptor may play a critical role in transformation from in situ to invasive basal subtype of high-grade ductal carcinoma of the breast. Hum Pathol 39:386–392CrossRefPubMedGoogle Scholar
  83. 83.
    Yu Q, Niu Y, Liu N, Zhang JZ, Liu TJ, Zhang RJ, Wang SL, Ding SM, Xiao XQ (2011) Expression of androgen receptor in breast cancer and its significance as a prognostic factor. Ann Oncol 22:1288–1294CrossRefPubMedGoogle Scholar
  84. 84.
    Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gómez H, Arteaga CL, Mills GB, Sanders ME, Pietenpol JA (2014) PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res 8(16):406CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Epidemiology and Prevention UnitFondazione IRCCS - Istituto Nazionale dei TumoriMilanItaly
  2. 2.Experimental Cancer Therapeutics, Department of OncologyMcMaster UniversityHamiltonCanada
  3. 3.Division of Endocrinology and MetabolismBeth Israel Medical CenterNew YorkUSA
  4. 4.Analytical Epidemiology and Health Impact UnitFondazione IRCCS, Istituto Nazionale dei TumoriMilanItaly

Personalised recommendations