JCT  Vol.4 No.4 , June 2013
Sex Steroids and Breast Cancer: An Overview
Abstract: Sex steroids, also known as sex hormones are synthesized naturally by the gonads (ovaries or testes). The two main classes of sex steroids, androgens and estrogens, are crucial hormones for the proper development and function of the body; they regulate sexual differentiation, the secondary sex characteristics, and sexual habits. They are also well known to influence many common cancers, especially hormonally driven cancers such as breast and prostate cancer. In this report, we review the association of sex steroids with cancer and the potential use of endocrine manipulation in cancer therapy as well as the limitations and challenges faced in this field.
Cite this paper: Z. Nahleh, J. Arenas and A. Tfayli, "Sex Steroids and Breast Cancer: An Overview," Journal of Cancer Therapy, Vol. 4 No. 4, 2013, pp. 851-856. doi: 10.4236/jct.2013.44097.

[1]   C. G. Brook, “Mechanism of Puberty,” Hormone Research, Vol. 51, Suppl. 3, 1999, pp. 52-54. doi:10.1159/000053162

[2]   K. Svechnikov and O. Soder, “Ontogeny of Gonadal Sex Steroids,” Best Practice & Research Clinical Endocrinology & Metabolism, Vol. 22, No. 1, 2008, pp. 95-106. doi:10.1016/j.beem.2007.09.002

[3]   Z. Hyde, L. Flicker, K. A. McCaul, O. P. Almeida, G. J. Hankey, S. A. Chubb, et al., “Associations between Testosterone Levels and Incident Prostate, Lung, and Colorectal Cancer. A Population-Based Study,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 21, No. 8, 2012, pp. 1319-1329. doi:10.1158/1055-9965.EPI-12-0129

[4]   S. E. Hankinson, G. A. Colditz and W. C. Willett, “Towards an Integrated Model for Breast Cancer Etiology: the Lifelong Interplay of Genes, Lifestyle, and Hormones,” Breast Cancer Research, Vol. 6, No. 5, 2004, pp. 213-218. doi:10.1186/bcr921

[5]   J. D. Figueroa and L. A. Brinton, “Unraveling Genes, Hormones, and Breast Cancer,” Journal of the National Cancer Institute, Vol. 104, No. 9, 2012, pp. 641-642. doi:10.1093/jnci/djs193

[6]   P. H. Gann, C. H. Hennekens, J. Ma, C. Longcope and M. J. Stampfer, “Prospective Study of Sex Hormone Levels and Risk of Prostate Cancer,” Journal of the National Cancer Institute, Vol. 88, No. 16, 1996, pp. 1118-1126. doi:10.1093/jnci/88.16.1118

[7]   T. Key, P. Appleby, I. Barnes and G. Reeves, “Endogenous Sex Hormones and Breast Cancer in Postmenopausal Women: Reanalysis of Nine Prospective Studies,” Journal of the National Cancer Institute, Vol. 94, No. 8, 2002, pp. 606-616. doi:10.1093/jnci/94.8.606

[8]   S. A. Missmer, A. H. Eliassen, R. L. Barbieri and S. E. Hankinson, “Endogenous Estrogen, Androgen, and Progesterone Concentrations and Breast Cancer Risk among Postmenopausal Women,” Journal of the National Cancer Institute, Vol. 96, No. 24, 2004, pp. 1856-1865. doi:10.1093/jnci/djh336

[9]   R. Kaaks, S. Rinaldi, T. J. Key, F. Berrino, P. H. Peeters, C. Biessy, et al., “Postmenopausal Serum Androgens, Oestrogens and Breast Cancer Risk: The European Prospective Investigation into Cancer and Nutrition,” Endocrine-Related Cancer, Vol. 12, No. 4, 2005, pp. 1071-1082. doi:10.1677/erc.1.01038

[10]   T. J. Key, P. N. Appleby, G. K. Reeves, A. Roddam, J. F. Dorgan, C. Longcope, et al., “Body Mass Index, Serum Sex Hormones, and Breast Cancer Risk in Postmenopausal Women,” Journal of the National Cancer Institute, Vol. 95, No. 16, 2003, pp. 1218-1226. doi:10.1093/jnci/djg022

[11]   S. Rinaldi, T. J. Key, P. H. Peeters, P. H. Lahmann, A. Lukanova, L. Dossus, et al., “Anthropometric Measures, Endogenous Sex Steroids and Breast Cancer Risk in Postmenopausal Women: A Study within the EPIC Cohort,” International Journal of Cancer, Vol. 118, No. 11, 2006, pp. 2832-2839. doi:10.1002/ijc.21730

[12]   Z. Nahleh and N. Tageja, “DHEA, Androgen Receptors, and Their Potential Role in Breast Cancer,” DHEA in Human Health and Aging, Ed., Taylor & Francis, Boca Raton, 2012.

[13]   H. G. Burger, E. C. Dudley, J. Cui, L. Dennerstein and J. L. Hopper, “A Prospective Longitudinal Study of Serum Testosterone, Dehydroepiandrosterone Sulfate, and Sex Hormone-Binding Globulin Levels through the Menopause Transition,” Journal of Clinical Endocrinology and Metabolism, Vol. 85, No. 8, 2000, pp. 2832-2838. doi:10.1210/jc.85.8.2832

[14]   A. Vermeulen, L. Verdonck and M. Kaufman, “A Critical Evaluation of Simple Methods for the Estimation of Free Testosterone in Serum,” Journal of Clinical Endocrinology and Metabolism, Vol. 84, No. 10, 1999, pp. 3666-3672. doi:10.1210/jc.84.10.3666

[15]   X. Xu, T. D. Veenstra, S. D. Fox, J. M. Roman, H. J. Issaq, R. Falk, et al., “Measuring Fifteen Endogenous Estrogens Simultaneously in Human Urine by High-Performance Liquid Chromatography-Mass Spectrometry,” Analytical Chemistry, Vol. 77, No. 20, 2005, pp. 6646-6654. doi:10.1021/ac050697c

[16]   K. Walker, O. Fletcher, N. Johnson, B. Coupland, V. A. McCormack, E. Folkerd, et al., “Premenopausal Mammographic Density in Relation to Cyclic Variations in Endogenous Sex Hormone Levels, Prolactin, and Insulin-Like Growth Factors,” Cancer Research, Vol. 69, No. 16, 2009, pp. 6490-6499. doi:10.1158/0008-5472.CAN-09-0280

[17]   N. Johnson, K. Walker, L. J. Gibson, N. Orr, E. Folkerd, B. Haynes, et al., “CYP3A Variation, Premenopausal Estrone Levels, and Breast Cancer Risk,” Journal of the National Cancer Institute, Vol. 104, No. 9, 2012, pp. 657-669. doi:10.1093/jnci/djs156

[18]   E. Winer, M. Morrow, K. Osborne, et al., “Cancer of the Breast,” In: V. T. Devita, S. Hellman and S. A. Rosenberg, Eds., Principles and Practice of Oncology, 6th Edition, J.B. Lippincott Co., Philadelphia, 2001, pp. 1651-1717

[19]   H. J. Burstein, A. A. Prestrud, J. Seidenfeld, H. Anderson, T. A. Buchholz, N. E. Davidson, et al., “American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women with Hormone Receptor-Positive Breast Cancer,” Journal of Clinical Oncology, Vol. 28, No. 23, 2010, pp. 3784-3796. doi:10.1200/JCO.2009.26.3756

[20]   R. C. Heel, R. N. Brogden, T. M. Speight and G. S. Avery, “Tamoxifen: A Review of Its Pharmacological Properties and Therapeutic Use in the Treatment of Breast Cancer,” Drugs, Vol. 16, No. 1, 1978, pp. 1-24. doi:10.2165/00003495-197816010-00001

[21]   “Effects of Adjuvant Tamoxifen and of Cytotoxic Therapy on Mortality in Early Breast Cancer. An Overview of 61 Randomized Trials among 28,896 Women. Early Breast Cancer Trialists’ Collaborative Group,” New England Journal of Medicine, Vol. 319, No. 26, 1988, pp. 1681-1692. doi:10.1056/NEJM198812293192601

[22]   Early Breast Cancer Trialists’ Collaborative Group, “Effects of Chemotherapy and Hormonal Therapy for Early Breast Cancer on Recurrence and 15-Year Survival: An Overview of the Randomized Trials,” Lancet, Vol. 365, No. 9472, 2005, pp. 1687-1717. doi:10.1016/S0140-6736(05)66544-0

[23]   P. Eifel, J. A. Axelson, J. Costa, J. Crowley, W. J. Curran, Jr., A. Deshler, et al., “National Institutes of Health Consensus Development Conference Statement: Adjuvant Therapy for Breast Cancer, November 1-3, 2000,” Journal of the National Cancer Institute, Vol. 93, No. 13, 2001, pp. 979-989. doi:10.1093/jnci/93.13.979

[24]   C. Davies, H. Pan, J. Godwin, R. Gray, R. Arriagada, V. Raina, et al., “Long-term Effects of Continuing Adjuvant Tamoxifen to 10 Years versus Stopping at 5 Years after Diagnosis of Oestrogen Receptor-Positive Breast Cancer: ATLAS, a Randomised Trial,” Lancet, Vol. 381, No. 9869, 2012, pp. 805-816.

[25]   “Suppression of Ovarian Function Plus Either Tamoxifen or Exemestane Compared with Tamoxifen Alone in Treating Premenopausal Women with Hormone-Responsive Breast Cancer (SOFT).”

[26]   M. Dowsett, J. Cuzick, J. Ingle, A. Coates, J. Forbes, J. Bliss, et al., “Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors versus Tamoxifen,” Journal of Clinical Oncology, Vol. 28, No. 3, 2010, pp. 509-518. doi:10.1200/JCO.2009.23.1274

[27]   S. R. Johnston and M. Dowsett, “Aromatase Inhibitors for Breast Cancer: Lessons from the Laboratory,” Nature Reviews Cancer, Vol. 3, No. 11, 2003, pp. 821-831. doi:10.1038/nrc1211

[28]   J. F. Forbes, J. Cuzick, A. Buzdar, A. Howell, J. S. Tobias and M. Baum, “Effect of Anastrozole and Tamoxifen as Adjuvant Treatment for Early-Stage Breast Cancer: 100-Month Analysis of the ATAC Trial,” Lancet Oncology, Vol. 9, No. 1, 2008, pp. 45-53. doi:10.1016/S1470-2045(07)70385-6

[29]   B. Thurlimann, A. Keshaviah, A. S. Coates, H. Mouridsen, L. Mauriac, J. F. Forbes, et al., “A Comparison of Letrozole and Tamoxifen in Postmenopausal Women with Early Breast Cancer,” The New England Journal of Medicine, Vol. 353, No. 26, 2005, pp. 2747-2757. doi:10.1056/NEJMoa052258

[30]   M. Kaufmann, W. Jonat, J. Hilfrich, H. Eidtmann, G. Gademann, I. Zuna, et al., “Improved Overall Survival in Postmenopausal Women with Early Breast Cancer after Anastrozole Initiated after Treatment with Tamoxifen Compared with Continued Tamoxifen: The ARNO 95 Study,” Journal of Clinical Oncology, Vol. 25, No. 19, 2007, pp. 2664-2670. doi:10.1200/JCO.2006.08.8054

[31]   R. C. Coombes, L. S. Kilburn, C. F. Snowdon, R. Paridaens, R. E. Coleman, S. E. Jones, et al., “Survival and Safety of Exemestane Versus Tamoxifen after 2 3 Years’ Tamoxifen Treatment (Intergroup Exemestane Study): A Randomised Controlled Trial,” Lancet, Vol. 369, No. 9561, 2007, pp. 559-570. doi:10.1016/S0140-6736(07)60200-1

[32]   National Institutes of Health, “Letrozole in Treating Women with Primary Breast Cancer Who Have Received 5 Years of Aromatase Inhibitor Therapy,” 2010. ct2/show/NCT00754845 US

[33]   National Institutes of Health, “Letrozole in Treating Women Who Have Received Hormone Therapy for Hormone Receptor-Positive Breast Cancer,” 2010.

[34]   Y. de Launoit, S. Dauvois, M. Dufour, J. Simard and F. Labrie, “Inhibition of Cell Cycle Kinetics and Proliferation by the Androgen 5 Alpha-Dihydrotestosterone and Antiestrogen N,n-butyl-N-methyl-11-[16' alpha-chloro-3', 17beta-dihydroxy-estra-1',3',5'-(10')triene-7'alpha-yl] Undecanamide in Human Breast Cancer ZR-75-1 Cells,” Cancer Research, Vol. 51, No. 11, 1991, pp. 2797-2802.

[35]   M. A. Greeve, R. K. Allan, J. M. Harvey, J. M. Bentel, “Inhibition of MCF-7 Breast Cancer Cell Proliferation by 5alpha-Dihydrotestosterone; A Role for p21 (Cip1/Waf1),” Journal of Molecular Endocrinology, Vol. 32, No. 3, 2004, pp. 793-810. doi:10.1677/jme.0.0320793

[36]   G. S. Gordan, A. Halden, Y. Horn, J. J. Fuery, R. J. Parsons and R. M. Walter, “Calusterone (7beta, 17alphaDimethyltestosterone) as Primary and Secondary Therapy of Advanced Breast Cancer,” Oncology, Vol. 28, No. 2, 1973, pp. 138-146. doi:10.1159/000224811

[37]   M. Kandouz, A. Lombet, J. Y. Perrot, D. Jacob, S. Carvajal, A. Kazem, et al., “Proapoptotic Effects of Antiestrogens, Progestins and Androgen in Breast Cancer Cells,” Journal of Steroid Biochemistry and Molecular Biology, Vol. 69, No. 1-6, 1999, pp. 463-471.

[38]   I. S. Goldenberg, N. Waters, R. S. Ravdin, F. J. Ansfield and A. Segaloff, “Androgenic Therapy for Advanced Breast cancer in Women. A Report of the Cooperative Breast Cancer Group,” Journal of the American Medical Association, Vol. 223, No. 11, 1973, pp. 1267-1268. doi:10.1001/jama.19 73.03220110045012