Breast Cancer Research and Treatment

, Volume 139, Issue 1, pp 1–11 | Cite as

Postmenopausal breast cancer, androgens, and aromatase inhibitors

  • C. Campagnoli
  • P. Pasanisi
  • I. Castellano
  • C. Abbà
  • T. Brucato
  • F. Berrino


Recent data can help to better define the long debated relationship between androgens and breast cancer (BC) after menopause. We reviewed the available literature data on: the origin of androgens after menopause, the association between circulating androgens and BC incidence and recurrence, the relationship between circulating and intratumoral hormones, the prognostic significance of the presence of androgen receptors (ARs) in the different BC subtypes, the androgen effect on BC cell lines, and the relationship between androgens and aromatase inhibitors. Epidemiological, clinical, and preclinical data on the role of androgens and of ARs on estrogen receptor (ER)-negative BC are somewhat controversial. However, most preclinical studies suggest that activated ARs, when present, have a proliferative effect, particularly in HER2 expressing cell lines, due to the cross-talk between AR and HER2 pathways. As regards ER-positive BC, epidemiological studies associate androgen levels with increased incidence and risk of recurrences, whilst clinical studies associate the AR positivity with a better prognosis. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also anti-proliferative, because AR activation restrains ER activity. The relative increase of androgenic action that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs), could contribute to their therapeutic efficacy in AR-positive cases. Available data, although defining a complex picture, suggest that circulating androgen levels are clinically relevant, particularly when AIs are used.


Postmenopausal breast cancer Androgens Androgen receptor Estrogens Aromatase inhibitors Metformin 



Breast cancer


Androgen receptor


Estrogen receptor


Aromatase inhibitor




Dehydroepiandrosterone sulfate


Sex hormone-binding globulin






E1 sulfate


Insulin-like growth factor











We thank Compagnia di San Paolo Foundation, Torino for funding. We thank Mrs. Maria Grazia Guerrini for excellent secretarial support.

Conflict of interest

The authors have declared no conflicts of interest.


  1. 1.
    Kotsopoulos J, Narod SA (2012) Androgens and breast cancer. Steroids 77:1–9PubMedCrossRefGoogle Scholar
  2. 2.
    Grattarola R, Secreto G, Recchione C (1975) Androgens in breast cancer. III. Breast cancer recurrences years after mastectomy and increased androgenic activity. Am J Obstet Gynecol 121:169–172PubMedGoogle Scholar
  3. 3.
    Secreto G, Venturelli E, Meneghini E, Greco M, Ferraris C, Gion M et al (2009) Testosterone and biological characteristics of breast cancers in postmenopausal women. Cancer Epidemiol Biomarkers Prev 18:2942–2948PubMedCrossRefGoogle Scholar
  4. 4.
    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 94:606–616PubMedCrossRefGoogle Scholar
  5. 5.
    Hickey TE, Robinson JL, Carroll JS, Tilley WD (2012) Minireview: the androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene? Mol Endocrinol 26:1252–1267PubMedCrossRefGoogle Scholar
  6. 6.
    Dimitrakakis C, Bondy C (2009) Androgens and the breast. Breast Cancer Res 11:212PubMedCrossRefGoogle Scholar
  7. 7.
    Farhat GN, Cummings SR, Chlebowski RT, Parimi N, Cauley JA, Rohan TE et al (2011) Sex hormone levels and risks of estrogen receptor-negative and estrogen receptor-positive breast cancers. J Natl Cancer Inst 103:562–570PubMedCrossRefGoogle Scholar
  8. 8.
    James RE, Lukanova A, Dossus L, Becker S, Rinaldi S, Tjonneland A et al (2011) Postmenopausal serum sex steroids and risk of hormone receptor-positive and -negative breast cancer: a nested case-control study. Cancer Prev Res (Phila) 4:1626–1635CrossRefGoogle Scholar
  9. 9.
    Sieri S, Krogh V, Bolelli G, Abagnato CA, Grioni S, Pala V et al (2009) Sex hormone levels, breast cancer risk, and cancer receptor status in postmenopausal women: the ORDET cohort. Cancer Epidemiol Biomarkers Prev 18:169–176PubMedCrossRefGoogle Scholar
  10. 10.
    Berrino F, Pasanisi P, Bellati C, Venturelli E, Krogh V, Mastroianni A et al (2005) Serum testosterone levels and breast cancer recurrence. Int J Cancer 113:499–502PubMedCrossRefGoogle Scholar
  11. 11.
    Micheli A, Meneghini E, Secreto G, Berrino F, Venturelli E, Cavalleri A et al (2007) Plasma testosterone and prognosis of postmenopausal breast cancer patients. J Clin Oncol 25:2685–2690PubMedCrossRefGoogle Scholar
  12. 12.
    Honma N, Saji S, Hirose M, Horiguchi S, Kuroi K, Hayashi S et al (2011) Sex steroid hormones in pairs of tumor and serum from breast cancer patients and pathobiological role of androstene-3beta, 17beta-diol. Cancer Sci 102:1848–1854PubMedCrossRefGoogle Scholar
  13. 13.
    Lonning PE, Haynes BP, Straume AH, Dunbier A, Helle H, Knappskog S et al (2011) Recent data on intratumor estrogens in breast cancer. Steroids 76:786–791PubMedCrossRefGoogle Scholar
  14. 14.
    Purohit A, Woo LW, Potter BV (2011) Steroid sulfatase: a pivotal player in estrogen synthesis and metabolism. Mol Cell Endocrinol 340:154–160PubMedCrossRefGoogle Scholar
  15. 15.
    Garay JP, Park BH (2012) Androgen receptor as a targeted therapy for breast cancer. Am J Cancer Res 2:434–445PubMedGoogle Scholar
  16. 16.
    Campagnoli C, Pasanisi P, Abba C, Ambroggio S, Biglia N, Brucato T et al (2012) Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study. Clin Breast Cancer 12:175–182PubMedCrossRefGoogle Scholar
  17. 17.
    Davis SR, Panjari M, Stanczyk FZ (2011) Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 96:1642–1653PubMedCrossRefGoogle Scholar
  18. 18.
    Davis SR, Braunstein GD (2012) Efficacy and safety of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women. J Sex Med 9:1134–1148PubMedCrossRefGoogle Scholar
  19. 19.
    Macedo LF, Guo Z, Tilghman SL, Sabnis GJ, Qiu Y, Brodie A (2006) Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res 66:7775–7782PubMedCrossRefGoogle Scholar
  20. 20.
    Takagi K, Miki Y, Nagasaki S, Hirakawa H, Onodera Y, Akahira J et al (2010) Increased intratumoral androgens in human breast carcinoma following aromatase inhibitor exemestane treatment. Endocr Relat Cancer 17:415–430PubMedCrossRefGoogle Scholar
  21. 21.
    Key TJ, Appleby PN, Reeves GK, Roddam AW, Helzlsouer KJ, Alberg AJ et al (2011) Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies. Br J Cancer 105:709–722PubMedCrossRefGoogle Scholar
  22. 22.
    Labrie F, Martel C, Balser J (2011) Wide distribution of the serum dehydroepiandrosterone and sex steroid levels in postmenopausal women: role of the ovary? Menopause 18:30–43PubMedCrossRefGoogle Scholar
  23. 23.
    Blouin K, Nadeau M, Mailloux J, Daris M, Lebel S, Luu-The V et al (2009) Pathways of adipose tissue androgen metabolism in women: depot differences and modulation by adipogenesis. Am J Physiol Endocrinol Metab 296:E244–E255PubMedCrossRefGoogle Scholar
  24. 24.
    Dalla Valle L, Toffolo V, Nardi A, Fiore C, Bernante P, Di Liddo R et al (2006) Tissue-specific transcriptional initiation and activity of steroid sulfatase complementing dehydroepiandrosterone sulfate uptake and intracrine steroid activations in human adipose tissue. J Endocrinol 190:129–139PubMedCrossRefGoogle Scholar
  25. 25.
    Cappola AR, Ratcliffe SJ, Bhasin S, Blackman MR, Cauley J, Robbins J et al (2007) Determinants of serum total and free testosterone levels in women over the age of 65 years. J Clin Endocrinol Metab 92:509–516PubMedCrossRefGoogle Scholar
  26. 26.
    Danforth KN, Eliassen AH, Tworoger SS, Missmer SA, Barbieri RL, Rosner BA et al (2010) The association of plasma androgen levels with breast, ovarian and endometrial cancer risk factors among postmenopausal women. Int J Cancer 126:199–207PubMedCrossRefGoogle Scholar
  27. 27.
    Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ (2007) Ovarian androgen production in postmenopausal women. J Clin Endocrinol Metab 92:3040–3043PubMedCrossRefGoogle Scholar
  28. 28.
    Patel SM, Iqbal N, Kaul S, Ratcliffe SJ, Rickels MR, Reilly MP et al (2010) Effects of metformin and leuprolide acetate on insulin resistance and testosterone levels in nondiabetic postmenopausal women: a randomized, placebo-controlled trial. Fertil Steril 94:2161–2166PubMedCrossRefGoogle Scholar
  29. 29.
    Patel SM, Ratcliffe SJ, Reilly MP, Weinstein R, Bhasin S, Blackman MR et al (2009) Higher serum testosterone concentration in older women is associated with insulin resistance, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab 94:4776–4784PubMedCrossRefGoogle Scholar
  30. 30.
    Markopoulos MC, Rizos D, Valsamakis G, Deligeoroglou E, Grigoriou O, Chrousos GP et al (2011) Hyperandrogenism in women with polycystic ovary syndrome persists after menopause. J Clin Endocrinol Metab 96:623–631PubMedCrossRefGoogle Scholar
  31. 31.
    Schmidt J, Brannstrom M, Landin-Wilhelmsen K, Dahlgren E (2011) Reproductive hormone levels and anthropometry in postmenopausal women with polycystic ovary syndrome (PCOS): a 21-year follow-up study of women diagnosed with PCOS around 50 years ago and their age-matched controls. J Clin Endocrinol Metab 96:2178–2185PubMedCrossRefGoogle Scholar
  32. 32.
    Maturana MA, Spritzer PM (2002) Association between hyperinsulinemia and endogenous androgen levels in peri- and postmenopausal women. Metabolism 51:238–243PubMedCrossRefGoogle Scholar
  33. 33.
    Palomba S, Falbo A, Zullo F, Orio F Jr (2009) Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev 30:1–50PubMedCrossRefGoogle Scholar
  34. 34.
    Carmina E (2006) Ovarian and adrenal hyperandrogenism. Ann N Y Acad Sci 1092:130–137PubMedCrossRefGoogle Scholar
  35. 35.
    Lanzone A, Fulghesu AM, Guido M, Fortini A, Caruso A, Mancuso S (1992) Differential androgen response to adrenocorticotropic hormone stimulation in polycystic ovarian syndrome: relationship with insulin secretion. Fertil Steril 58:296–301PubMedGoogle Scholar
  36. 36.
    Diamanti-Kandarakis E, Economou F, Palimeri S, Christakou C (2010) Metformin in polycystic ovary syndrome. Ann N Y Acad Sci 1205:192–198PubMedCrossRefGoogle Scholar
  37. 37.
    Rinaldi S, Peeters PH, Bezemer ID, Dossus L, Biessy C, Sacerdote C et al (2006) Relationship of alcohol intake and sex steroid concentrations in blood in pre- and post-menopausal women: the European Prospective Investigation into Cancer and Nutrition. Cancer Causes Control 17:1033–1043PubMedCrossRefGoogle Scholar
  38. 38.
    Pasqualini JR, Chetrite G (2012) Hormonal enzymatic systems in normal and cancerous human breast: control, prognostic factors, and clinical applications. Horm Mol Biol Clin Invest 9:25–63Google Scholar
  39. 39.
    Suzuki T, Miki Y, Takagi K, Hirakawa H, Moriya T, Ohuchi N et al (2010) Androgens in human breast carcinoma. Med Mol Morphol 43:75–81PubMedCrossRefGoogle Scholar
  40. 40.
    Recchione C, Venturelli E, Manzari A, Cavalleri A, Martinetti A, Secreto G (1995) Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues. J Steroid Biochem Mol Biol 52:541–546PubMedCrossRefGoogle Scholar
  41. 41.
    Haynes BP, Straume AH, Geisler J, A’Hern R, Helle H, Smith IE et al (2010) Intratumoral estrogen disposition in breast cancer. Clin Cancer Res 16:1790–1801PubMedCrossRefGoogle Scholar
  42. 42.
    Lonning PE, Helle H, Duong NK, Ekse D, Aas T, Geisler J (2009) Tissue estradiol is selectively elevated in receptor positive breast cancers while tumour estrone is reduced independent of receptor status. J Steroid Biochem Mol Biol 117:31–41PubMedCrossRefGoogle Scholar
  43. 43.
    Key TJ (2011) Endogenous oestrogens and breast cancer risk in premenopausal and postmenopausal women. Steroids 76:812–815PubMedCrossRefGoogle Scholar
  44. 44.
    Millikan RC, Newman B, Tse CK, Moorman PG, Conway K, Dressler LG et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109:123–139PubMedCrossRefGoogle Scholar
  45. 45.
    Yang XR, Sherman ME, Rimm DL, Lissowska J, Brinton LA, Peplonska B et al (2007) Differences in risk factors for breast cancer molecular subtypes in a population-based study. Cancer Epidemiol Biomarkers Prev 16:439–443PubMedCrossRefGoogle Scholar
  46. 46.
    Dorgan JF, Stanczyk FZ, Longcope C, Stephenson HE Jr, Chang L, Miller R et al (1997) Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3 beta, 17 beta-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 6:177–181PubMedGoogle Scholar
  47. 47.
    Kaaks R, Rinaldi S, Key TJ, Berrino F, Peeters PH, Biessy C et al (2005) Postmenopausal serum androgens, oestrogens and breast cancer risk: the European prospective investigation into cancer and nutrition. Endocr Relat Cancer 12:1071–1082PubMedCrossRefGoogle Scholar
  48. 48.
    Emond JA, Patterson RE, Natarajan L, Laughlin GA, Gold EB, Pierce JP (2011) Sex hormone concentrations and the risk of breast cancer recurrence in postmenopausal women without hot flashes. Cancer Epidemiol Biomarkers Prev 20:939–945PubMedCrossRefGoogle Scholar
  49. 49.
    Rock CL, Flatt SW, Laughlin GA, Gold EB, Thomson CA, Natarajan L et al (2008) Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev 17:614–620PubMedCrossRefGoogle Scholar
  50. 50.
    Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA et al (2010) Diabetes and cancer: a consensus report. CA Cancer J Clin 60:207–221PubMedCrossRefGoogle Scholar
  51. 51.
    Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Martin-Castillo B, Menendez JA (2010) Metformin and energy metabolism in breast cancer: from insulin physiology to tumour-initiating stem cells. Curr Mol Med 10:674–691PubMedCrossRefGoogle Scholar
  52. 52.
    Duggan C, Irwin ML, Xiao L, Henderson KD, Smith AW, Baumgartner RN et al (2011) Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J Clin Oncol 29:32–39PubMedCrossRefGoogle Scholar
  53. 53.
    Goodwin PJ, Ennis M, Pritchard KI, Trudeau ME, Koo J, Madarnas Y et al (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20:42–51PubMedCrossRefGoogle Scholar
  54. 54.
    Gunter MJ, Hoover DR, Yu H, Wassertheil-Smoller S, Rohan TE, Manson JE et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101:48–60PubMedCrossRefGoogle Scholar
  55. 55.
    Sieri S, Muti P, Claudia A, Berrino F, Pala V, Grioni S et al (2012) Prospective study on the role of glucose metabolism in breast cancer occurrence. Int J Cancer 130:921–929PubMedCrossRefGoogle Scholar
  56. 56.
    Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623PubMedCrossRefGoogle Scholar
  57. 57.
    Lorincz AM, Sukumar S (2006) Molecular links between obesity and breast cancer. Endocr Relat Cancer 13:279–292PubMedCrossRefGoogle Scholar
  58. 58.
    Falk RT, Gentzschein E, Stanczyk FZ, Garcia-Closas M, Figueroa JD, Ioffe OB et al (2012) Sex steroid hormone levels in breast adipose tissue and serum in postmenopausal women. Breast Cancer Res Treat 131:287–294PubMedCrossRefGoogle Scholar
  59. 59.
    Micello D, Marando A, Sahnane N, Riva C, Capella C, Sessa F (2010) Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers. Virchows Arch 457:467–476PubMedCrossRefGoogle Scholar
  60. 60.
    Naderi A, Hughes-Davies L (2008) A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer. Neoplasia 10:542–548PubMedGoogle Scholar
  61. 61.
    Park S, Koo JS, Kim MS, Park HS, Lee JS, Lee JS et al (2011) Androgen receptor expression is significantly associated with better outcomes in estrogen receptor-positive breast cancers. Ann Oncol 22:1755–1762PubMedCrossRefGoogle Scholar
  62. 62.
    He J, Peng R, Yuan Z, Wang S, Peng J, Lin G et al (2012) Prognostic value of androgen receptor expression in operable triple-negative breast cancer: a retrospective analysis based on a tissue microarray. Med Oncol 29:406–410PubMedCrossRefGoogle Scholar
  63. 63.
    Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K et al (2011) Androgen receptor expression and breast cancer survival in postmenopausal women. Clin Cancer Res 17:1867–1874PubMedCrossRefGoogle Scholar
  64. 64.
    Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH et al (2010) Expression of androgen receptors in primary breast cancer. Ann Oncol 21:488–492PubMedCrossRefGoogle Scholar
  65. 65.
    Rakha EA, El-Sayed ME, Green AR, Lee AH, Robertson JF, Ellis IO (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32PubMedCrossRefGoogle Scholar
  66. 66.
    Tang D, Xu S, Zhang Q, Zhao W (2012) The expression and clinical significance of the androgen receptor and E-cadherin in triple-negative breast cancer. Med Oncol 29:526–533PubMedCrossRefGoogle Scholar
  67. 67.
    Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ (2003) Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Am J Clin Pathol 120:725–731PubMedCrossRefGoogle Scholar
  68. 68.
    Castellano I, Allia E, Accortanzo V, Vandone AM, Chiusa L, Arisio R et al (2010) Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers. Breast Cancer Res Treat 124:607–617PubMedCrossRefGoogle Scholar
  69. 69.
    Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R (2010) Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 23:205–212PubMedCrossRefGoogle Scholar
  70. 70.
    Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM et al (2009) Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res 69:6131–6140PubMedCrossRefGoogle Scholar
  71. 71.
    Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, Carey M, Agarwal R, Meric-Berstam F et al (2009) Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res 15:2472–2478PubMedCrossRefGoogle Scholar
  72. 72.
    Peter MB, Shaaban AM (2011) Investigating and critically appraising the expression and potential role of androgen receptor in breast carcinoma. Horm Mol Biol Clin Invest 7:273–278Google Scholar
  73. 73.
    De Amicis F, Thirugnansampanthan J, Cui Y, Selever J, Beyer A, Parra I et al (2010) Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat 121:1–11PubMedCrossRefGoogle Scholar
  74. 74.
    Bryan RM, Mercer RJ, Bennett RC, Rennie GC, Lie TH, Morgan FJ (1984) Androgen receptors in breast cancer. Cancer 54:2436–2440PubMedCrossRefGoogle Scholar
  75. 75.
    Garreau JR, Muller P, Pommier R, Pommier S (2006) Transgenic introduction of androgen receptor into estrogen-receptor-, progesterone-receptor-, and androgen-receptor-negative breast cancer cells renders them responsive to hormonal manipulation. Am J Surg 191:576–580PubMedCrossRefGoogle Scholar
  76. 76.
    Hardin C, Pommier R, Calhoun K, Muller P, Jackson T, Pommier S (2007) A new hormonal therapy for estrogen receptor-negative breast cancer. World J Surg 31:1041–1046PubMedCrossRefGoogle Scholar
  77. 77.
    Lopez-Marure R, Contreras PG, Dillon JS (2011) Effects of dehydroepiandrosterone on proliferation, migration, and death of breast cancer cells. Eur J Pharmacol 660:268–274PubMedCrossRefGoogle Scholar
  78. 78.
    Nahleh Z (2008) Androgen receptor as a target for the treatment of hormone receptor-negative breast cancer: an unchartered territory. Future Oncol 4:15–21PubMedCrossRefGoogle Scholar
  79. 79.
    Toth-Fejel S, Cheek J, Calhoun K, Muller P, Pommier RF (2004) Estrogen and androgen receptors as comediators of breast cancer cell proliferation: providing a new therapeutic tool. Arch Surg 139:50–54PubMedCrossRefGoogle Scholar
  80. 80.
    Garay JP, Karakas B, Abukhdeir AM, Cosgrove DP, Gustin JP, Higgins MJ et al (2012) The growth response to androgen receptor signaling in ERalpha-negative human breast cells is dependent on p21 and mediated by MAPK activation. Breast Cancer Res 14:R27PubMedCrossRefGoogle Scholar
  81. 81.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767PubMedCrossRefGoogle Scholar
  82. 82.
    Moore NL, Buchanan G, Harris JM, Selth LA, Bianco-Miotto T, Hanson AR et al (2012) An androgen receptor mutation in the MDA-MB-453 cell line model of molecular apocrine breast cancer compromises receptor activity. Endocr Relat Cancer 19:599–613PubMedCrossRefGoogle Scholar
  83. 83.
    Naderi A, Chia KM, Liu J (2011) Synergy between inhibitors of androgen receptor and MEK has therapeutic implications in estrogen receptor-negative breast cancer. Breast Cancer Res 13:R36PubMedCrossRefGoogle Scholar
  84. 84.
    Ni M, Chen Y, Lim E, Wimberly H, Bailey ST, Imai Y et al (2011) Targeting androgen receptor in estrogen receptor-negative breast cancer. Cancer Cell 20:119–131PubMedCrossRefGoogle Scholar
  85. 85.
    Ando S, De AF, Rago V, Carpino A, Maggiolini M, Panno ML et al (2002) Breast cancer: from estrogen to androgen receptor. Mol Cell Endocrinol 193:121–128PubMedCrossRefGoogle Scholar
  86. 86.
    Birrell SN, Butler LM, Harris JM, Buchanan G, Tilley WD (2007) Disruption of androgen receptor signaling by synthetic progestins may increase risk of developing breast cancer. FASEB J 21:2285–2293PubMedCrossRefGoogle Scholar
  87. 87.
    Sonne-Hansen K, Lykkesfeldt AE (2005) Endogenous aromatization of testosterone results in growth stimulation of the human MCF-7 breast cancer cell line. J Steroid Biochem Mol Biol 93:25–34PubMedCrossRefGoogle Scholar
  88. 88.
    Need EF, Selth LA, Harris TJ, Birrell SN, Tilley WD, Buchanan G (2012) Research resource: interplay between the genomic and transcriptional networks of androgen receptor and estrogen receptor alpha in luminal breast cancer cells. Mol Endocrinol 26:1941–1952PubMedCrossRefGoogle Scholar
  89. 89.
    Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ et al (1995) Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol 52:459–467PubMedCrossRefGoogle Scholar
  90. 90.
    Hackenberg R, Schulz KD (1996) Androgen receptor mediated growth control of breast cancer and endometrial cancer modulated by antiandrogen- and androgen-like steroids. J Steroid Biochem Mol Biol 56:113–117PubMedCrossRefGoogle Scholar
  91. 91.
    Suzuki T, Miki Y, Moriya T, Akahira J, Ishida T, Hirakawa H et al (2007) 5Alpha-reductase type 1 and aromatase in breast carcinoma as regulators of in situ androgen production. Int J Cancer 120:285–291PubMedCrossRefGoogle Scholar
  92. 92.
    Chanplakorn N, Chanplakorn P, Suzuki T, Ono K, Wang L, Chan MS et al (2011) Increased 5alpha-reductase type 2 expression in human breast carcinoma following aromatase inhibitor therapy: the correlation with decreased tumor cell proliferation. Horm Cancer 2:73–81PubMedCrossRefGoogle Scholar
  93. 93.
    Boccuzzi G, Brignardello E, dimonaco M, Forte C, Leonardi L, Pizzini A (1992) Influence of dehydroepiandrosterone and 5-en-androstene-3 beta, 17 beta-diol on the growth of MCF-7 human breast cancer cells induced by 17 beta-estradiol. Anticancer Res 12:799–803PubMedGoogle Scholar
  94. 94.
    Bajetta E, Martinetti A, Zilembo N, Pozzi P, La Torre I, Ferrari L et al (2002) Biological activity of anastrozole in postmenopausal patients with advanced breast cancer: effects on estrogens and bone metabolism. Ann Oncol 13:1059–1066PubMedCrossRefGoogle Scholar
  95. 95.
    Stanway SJ, Palmieri C, Stanczyk FZ, Folkerd EJ, Dowsett M, Ward R et al (2011) Effect of tamoxifen or anastrozole on steroid sulfatase activity and serum androgen concentrations in postmenopausal women with breast cancer. Anticancer Res 31:1367–1372PubMedGoogle Scholar
  96. 96.
    Rossi E, Morabito A, Di RF, Esposito G, Gravina A, Labonia V et al (2009) Endocrine effects of adjuvant letrozole compared with tamoxifen in hormone-responsive postmenopausal patients with early breast cancer: the HOBOE trial. J Clin Oncol 27:3192–3197PubMedCrossRefGoogle Scholar
  97. 97.
    Loves S, Ruinemans-Koerts J, de Boer H (2008) Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol 158:741–747PubMedCrossRefGoogle Scholar
  98. 98.
    Gallicchio L, Macdonald R, Wood B, Rushovich E, Helzlsouer KJ (2011) Androgens and musculoskeletal symptoms among breast cancer patients on aromatase inhibitor therapy. Breast Cancer Res Treat 130:569–577PubMedCrossRefGoogle Scholar
  99. 99.
    van Londen GJ, Perera S, Vujevich K, Rastogi P, Lembersky B, Brufsky A et al (2011) The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer. Breast Cancer Res Treat 125:441–446PubMedCrossRefGoogle Scholar
  100. 100.
    Morris KT, Toth-Fejel S, Schmidt J, Fletcher WS, Pommier RF (2001) High dehydroepiandrosterone-sulfate predicts breast cancer progression during new aromatase inhibitor therapy and stimulates breast cancer cell growth in tissue culture: a renewed role for adrenalectomy. Surgery 130:947–953PubMedCrossRefGoogle Scholar
  101. 101.
    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
  102. 102.
    Kenemans P, van der Mooren MJ (2012) Androgens and breast cancer risk. Gynecol Endocrinol 28(Suppl 1):46–49PubMedCrossRefGoogle Scholar
  103. 103.
    Wylie K, Rees M, Hackett G, Anderson R, Bouloux PM, Cust M et al (2010) Androgens, health and sexuality in women and men. Maturitas 67:275–289PubMedCrossRefGoogle Scholar
  104. 104.
    Berrino F, Bellati C, Secreto G, Camerini E, Pala V, Panico S et al (2001) Reducing bioavailable sex hormones through a comprehensive change in diet: the diet and androgens (DIANA) randomized trial. Cancer Epidemiol Biomarkers Prev 10:25–33PubMedGoogle Scholar
  105. 105.
    Villarini A, Pasanisi P, Traina A, Mano MP, Bonanni B, Panico S et al (2012) Lifestyle and breast cancer recurrences: the DIANA-5 trial. Tumori 98:1–18PubMedGoogle Scholar
  106. 106.
    Byers T, Sedjo RL (2011) Does intentional weight loss reduce cancer risk? Diabetes Obes Metab 13:1063–1072PubMedCrossRefGoogle Scholar
  107. 107.
    Campbell KL, Foster-Schubert KE, Alfano CM, Wang CC, Wang CY, Duggan CR et al (2012) Reduced-calorie dietary weight loss, exercise, and sex hormones in postmenopausal women: randomized controlled trial. J Clin Oncol 30:2314–2326PubMedCrossRefGoogle Scholar
  108. 108.
    Kim C, Kong S, Laughlin GA, Golden SH, Mather KJ, Nan B et al (2012) Endogenous sex hormone changes in postmenopausal women in the diabetes prevention program. J Clin Endocrinol Metab 97:2853–2861PubMedCrossRefGoogle Scholar
  109. 109.
    Liedtke S, Schmidt ME, Becker S, Kaaks R, Zaineddin AK, Buck K et al (2011) Physical activity and endogenous sex hormones in postmenopausal women: to what extent are observed associations confounded or modified by BMI? Cancer Causes Control 22:81–89PubMedCrossRefGoogle Scholar
  110. 110.
    Hawley JA, Lessard SJ (2008) Exercise training-induced improvements in insulin action. Acta Physiol (Oxf) 192:127–135CrossRefGoogle Scholar
  111. 111.
    Irwin ML (2009) Physical activity interventions for cancer survivors. Br J Sports Med 43:32–38PubMedCrossRefGoogle Scholar
  112. 112.
    Ligibel JA, Campbell N, Partridge A, Chen WY, Salinardi T, Chen H et al (2008) Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26:907–912PubMedCrossRefGoogle Scholar
  113. 113.
    Birks S, Peeters A, Backholer K, O’Brien P, Brown W (2012) A systematic review of the impact of weight loss on cancer incidence and mortality. Obes Rev 13:868–891PubMedCrossRefGoogle Scholar
  114. 114.
    Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B et al (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3:1451–1461CrossRefGoogle Scholar
  115. 115.
    Dowling RJ, Niraula S, Stambolic V, Goodwin PJ (2012) Metformin in cancer: translational challenges. J Mol Endocrinol 48:R31–R43PubMedCrossRefGoogle Scholar
  116. 116.
    Pierotti MA, Berrino F, Gariboldi M, Melani C, Mogavero A, Negri T et al (2013) Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene 32:1475–1487PubMedCrossRefGoogle Scholar
  117. 117.
    Chlebowski RT, McTiernan A, Wactawski-Wende J, Manson JE, Aragaki AK, Rohan T et al (2012) Diabetes, metformin, and breast cancer in postmenopausal women. J Clin Oncol 30:2844–2852PubMedCrossRefGoogle Scholar
  118. 118.
    Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT (2012) Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat 135:639–646PubMedCrossRefGoogle Scholar
  119. 119.
    Gucalp A, Traina TA (2010) Triple-negative breast cancer: role of the androgen receptor. Cancer J 16:62–65PubMedCrossRefGoogle Scholar
  120. 120.
    Hudis CA, Gianni L (2011) Triple-negative breast cancer: an unmet medical need. Oncologist 16(Suppl 1):1–11PubMedCrossRefGoogle Scholar
  121. 121.
    He X, Esteva FJ, Ensor J, Hortobagyi GN, Lee MH, Yeung SC (2012) Metformin and thiazolidinediones are associated with improved breast cancer-specific survival of diabetic women with HER2+ breast cancer. Ann Oncol 23:1771–1780PubMedCrossRefGoogle Scholar
  122. 122.
    Lonning PE (2009) Additive endocrine therapy for advanced breast cancer—back to the future. Acta Oncol 48:1092–1101PubMedCrossRefGoogle Scholar
  123. 123.
    Esteva FJ, Moulder SL, Gonzalez-Angulo AM, Ensor J, Murray JL, Green MC et al (2013) Phase I trial of exemestane in combination with metformin and rosiglitazone in nondiabetic obese postmenopausal women with hormone receptor-positive metastatic breast cancer. Cancer Chemother Pharmacol 71:63–72PubMedCrossRefGoogle Scholar
  124. 124.
    Davis SR, Moreau M, Kroll R, Bouchard C, Panay N, Gass M et al (2008) Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med 359:2005–2017PubMedCrossRefGoogle Scholar
  125. 125.
    Simpson ER, Misso M, Hewitt KN, Hill RA, Boon WC, Jones ME et al (2005) Estrogen—the good, the bad, and the unexpected. Endocr Rev 26:322–330PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • C. Campagnoli
    • 1
  • P. Pasanisi
    • 2
    • 4
  • I. Castellano
    • 3
  • C. Abbà
    • 1
  • T. Brucato
    • 1
  • F. Berrino
    • 2
  1. 1.Unit of Endocrinological GynecologyOspedale Ginecologico Sant’Anna di TorinoTurinItaly
  2. 2.Epidemiology UnitFondazione IRCCS, Istituto Nazionale dei Tumori di MilanoMilanItaly
  3. 3.Department of Medical SciencesUniversità degli Studi di TorinoTurinItaly
  4. 4.Department of Predictive & Preventive MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly

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