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Progesterone signalling in breast cancer: a neglected hormone coming into the limelight

Key Points

  • Mutations are not always sufficient to drive breast carcinogenesis but additional factors determine whether genetically altered cells progress to the state during which they provoke clinically manifest disease.

  • The ovarian steroid hormones, 17β-oestradiol and progesterone, are pivotal in the control of breast development and physiology and are intimately linked to mammary carcinogenesis. Their respective roles in vivo have begun to be dissected in the mouse model.

  • 17β-oestradiol and progesterone act on a subset of cells that express the respective receptors and elicit paracrine signalling.

  • Progesterone has emerged as the major mitogen in the adult mammary epithelium in both mice and humans.

  • The major proliferative control axis progesterone–receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is conserved between mice and humans.

  • Interfering with progesterone receptor (PR) signalling and paracrine signalling holds promise for breast cancer prevention and therapy.

Abstract

Understanding the biology of the breast and how ovarian hormones impinge on it is key to rational new approaches in breast cancer prevention and therapy. Because of the success of selective oestrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors in breast cancer treatment, oestrogens have long received the most attention. Early progesterone receptor (PR) antagonists, however, were dismissed because of severe side effects, but awareness is now increasing that progesterone is an important hormone in breast cancer. Oestrogen receptor-α (ERα) signalling and PR signalling have distinct roles in normal mammary gland biology in mice; both ERα and PR delegate many of their biological functions to distinct paracrine mediators. If the findings in the mouse model translate to humans, new preventive and therapeutic perspectives might open up.

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Figure 1: The menstrual cycle: serum hormone levels during a typical menstrual cycle together with changes in the breast.
Figure 2: Whole-mount stereographs of mouse inguinal mammary glands depicting distinct stages of mammary gland development.
Figure 3: Tissue recombination approach.
Figure 4: Model: effect of menstrual cycles on breast cancer risk based on work in mouse models.
Figure 5: Models of cell-intrinsic and paracrine mechanisms of progesterone-induced cell proliferation in the mouse mammary epithelium.
Figure 6: Model of breast carcinogenesis.

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References

  1. Lakhani, S. R., Ellis, I. O., Schnitt, S. J., Tan, P. H. & van de Vijver, M. J. in WHO Classification of Tumors of the Breast. (eds Tavassoli, F. & Devilee, P.) 13–59 (IARC Press, 2012).

    Google Scholar 

  2. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

  3. Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nature Rev. Cancer 12, 323–334 (2012).

    CAS  Google Scholar 

  5. Almendro, V., Marusyk, A. & Polyak, K. Cellular heterogeneity and molecular evolution in cancer. Annu. Rev. Pathol. 8, 277–302 (2012).

    PubMed  Google Scholar 

  6. Nielsen, M., Thomsen, J. L., Primdahl, S., Dyreborg, U. & Andersen, J. A. Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. Br. J. Cancer 56, 814–819 (1987). This study shows that about 30% of women in their forties have DCIS or DCIS-like lesions in their breasts.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Buerger, H. et al. Comparative genomic hybridization of ductal carcinoma in situ of the breast-evidence of multiple genetic pathways. J. Pathol. 187, 396–402 (1999).

    CAS  PubMed  Google Scholar 

  8. Nandi, S. Endocrine control of mammary-gland development in the C3H/He Crgl mouse. J. Natl Cancer Inst. 21, 1039–1063 (1958).

    CAS  PubMed  Google Scholar 

  9. Lyons, W. R. Hormonal synergism in mammary growth. Proc. R. Soc. Lond. B Biol. Sci. 149, 303–325 (1958).

    CAS  PubMed  Google Scholar 

  10. MacMahon, B. et al. Age at first birth and breast cancer risk. Bull. World Health Organ. 43, 209–221 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Colditz, G. A., Rosner, B. A., Chen, W. Y., Holmes, M. D. & Hankinson, S. E. Risk factors for breast cancer according to estrogen and progesterone receptor status. J. Natl Cancer Inst. 96, 218–228 (2004).

    CAS  PubMed  Google Scholar 

  12. Pike, M. C. Krailo, M. D., Henderson, B. E., Casagrande, J.T. & Hoel, D. G. 'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer. Nature 303, 767–770 (1983). This early study highlights that, unlike other cancers, breast cancer does not simply increase exponentially with age and proposes a model for 'breast tissue age'.

    CAS  PubMed  Google Scholar 

  13. Masters, J. R., Drife, J. O. & Scarisbrick, J. J. Cyclic Variation of DNA synthesis in human breast epithelium. J. Natl Cancer Inst. 58, 1263–1265 (1977).

    CAS  PubMed  Google Scholar 

  14. Longacre, T. A. & Bartow, S. A. A correlative morphologic study of human breast and endometrium in the menstrual cycle. Am. J. Surg. Pathol. 10, 382–393 (1986).

    CAS  PubMed  Google Scholar 

  15. Wellings, S. R. & Jensen, H. M. On the origin and progression of ductal carcinoma in the human breast. J. Natl Cancer Inst. 50, 1111–1118 (1973).

    CAS  PubMed  Google Scholar 

  16. Beatson, G. T. On the treatment of inoperable cases of carcinoma of the mamma: suggestions for a new method of treatment, with illustrative cases. Lancet, 104–107 (1896).

    Google Scholar 

  17. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365, 1687–1717 (2005).

  18. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 347, 1713–1727 (1996).

  19. Anderson, G. L. et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial. Lancet Oncol. 13, 476–486 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Beral, V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419–427 (2003).

    CAS  PubMed  Google Scholar 

  21. Chlebowski, R. T. et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304, 1684–1692 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Rossouw, J. E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 288, 321–333 (2002).

    CAS  PubMed  Google Scholar 

  23. Hofseth, L. J. et al. Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J. Clin. Endocrinol. Metab. 84, 4559–4565 (1999).

    CAS  PubMed  Google Scholar 

  24. Fournier, A., Berrino, F. & Clavel-Chapelon, F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res. Treat. 107, 103–111 (2008).

    CAS  PubMed  Google Scholar 

  25. Fournier, A., Berrino, F., Riboli, E., Avenel, V. & Clavel-Chapelon, F. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int. J. Cancer 114, 448–454 (2005).

    CAS  PubMed  Google Scholar 

  26. Sitruk-Ware, R. Pharmacological profile of progestins. Maturitas 47, 277–283 (2004).

    CAS  PubMed  Google Scholar 

  27. Farhat, G. N., Walker, R., Buist, D. S., Onega, T. & Kerlikowske, K. Changes in invasive breast cancer and ductal carcinoma in situ rates in relation to the decline in hormone therapy use. J. Clin. Oncol. 28, 5140–5146 (2010).

    PubMed  PubMed Central  Google Scholar 

  28. Chlebowski, R. T. et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N. Engl. J. Med. 360, 573–587 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. McCormack, V. A. & dos Santos Silva, I. Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol. Biomarkers Prev. 15, 1159–1169 (2006).

    PubMed  Google Scholar 

  30. Boyd, N. F. et al. Mammographic density and the risk and detection of breast cancer. N. Engl. J. Med. 356, 227–236 (2007).

    CAS  PubMed  Google Scholar 

  31. Lundstrom, E. et al. Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density. Am. J. Obstet. Gynecol. 186, 717–722 (2002).

    CAS  PubMed  Google Scholar 

  32. Vachon, C. M., Sellers, T. A., Vierkant, R. A., Wu, F. F. & Brandt, K. R. Case-control study of increased mammographic breast density response to hormone replacement therapy. Cancer Epidemiol. Biomarkers Prev. 11, 1382–1388 (2002).

    CAS  PubMed  Google Scholar 

  33. Greendale, G. A. et al. Postmenopausal hormone therapy and change in mammographic density. J. Natl Cancer Inst. 95, 30–37 (2003).

    CAS  PubMed  Google Scholar 

  34. Daniel, C. W., Silberstein, G. B. & Strickland, P. Direct action of 17 β-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiography. Cancer Res. 47, 6052–6057 (1987).

    CAS  PubMed  Google Scholar 

  35. Beleut, M. et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc. Natl Acad. Sci. USA 107, 2989–2994 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang, S., Counterman, L. J. & Haslam, S. Z. Progesterone action in normal mouse mammary gland. Endocrinology 127, 2183–2189 (1990).

    CAS  PubMed  Google Scholar 

  37. Haslam, S. Z. & Shyamala, G. Effect of oestradiol on progesterone receptors in normal mammary glands and its relationship with lactation. Biochem. J. 182, 127–131 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Aupperlee, M. D. & Haslam, S. Z. Differential hormonal regulation and function of progesterone receptor isoforms in normal adult mouse mammary gland. Endocrinology 148, 2290–2300 (2007).

    CAS  PubMed  Google Scholar 

  39. Lydon, J. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9, 2266–2278 (1995).

    CAS  PubMed  Google Scholar 

  40. Dupont, S. et al. Effect of single and compound knockouts of estrogen receptors α (ERα) and β (ERβ) on mouse reproductive phenotypes. Development 127, 4277–4291 (2000).

    CAS  PubMed  Google Scholar 

  41. Mallepell, S., Krust, A., Chambon, P. & Brisken, C. Paracrine signaling through the epithelial estrogen receptor α is required for proliferation and morphogenesis in the mammary gland. Proc. Natl Acad. Sci. USA 103, 2196–2201 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Brisken, C. et al. A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc. Natl Acad. Sci. USA 95, 5076–5081 (1998). This study provided genetic evidence that epithelial intrinsic progesterone signalling is important for mammary gland side branching and that progesterone can function by paracrine mechanisms.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Brisken, C. & O'Malley, B. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol. 2, a003178 (2011).

    Google Scholar 

  44. Walmer, D. K., Wrona, M. A., Hughes, C. L. & Nelson, K. G. Lactoferrin expression in the mouse reproductive tract during the natural estrous cycle: correlation with circulating estradiol and progesterone. Endocrinology 131, 1458–1466 (1992).

    CAS  PubMed  Google Scholar 

  45. Caligioni, C. S. Assessing reproductive status/stages in mice. Curr. Protoc. Neurosci. 4, Appendix 4I (2009).

    PubMed  Google Scholar 

  46. Chow, J. D., Simpson, E. R. & Boon, W. C. Alternative 5′-untranslated first exons of the mouse Cyp19A1 (aromatase) gene. J. Steroid Biochem. Mol. Biol. 115, 115–125 (2009).

    CAS  PubMed  Google Scholar 

  47. Tanos, T. et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci. Transl. Med. 5, 182ra55 (2013).

    PubMed  Google Scholar 

  48. Clarke, R. B., Howell, A., Potten, C. S. & Anderson, E. Dissociation between steroid receptor expression and cell proliferation in the human breast. Cancer Res. 57, 4987–4991 (1997). This study showed that in the normal human breast epithelium, cell proliferation and hormone receptor expression are dissociated, whereas in breast cancer samples ERα+ cells frequently proliferate.

    CAS  PubMed  Google Scholar 

  49. Grimm, S. L. et al. Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development. Mol. Endocrinol. 16, 2675–2691 (2002).

    CAS  PubMed  Google Scholar 

  50. Seagroves, T. N., Lydon, J. P., Hovey, R. C., Vonderhaar, B. K. & Rosen, J. M. C/EBPβ (CCAAT/enhancer binding protein) controls cell fate determination during mammary gland development. Mol. Endocrinol. 14, 359–368 (2000).

    CAS  PubMed  Google Scholar 

  51. Russo, J., Ao, X., Grill, C. & Russo, I. H. Pattern of distribution of cells positive for estrogen receptor α and progesterone receptor in relation to proliferating cells in the mammary gland [In Process Citation]. Breast Cancer Res. Treat. 53, 217–227 (1999).

    CAS  PubMed  Google Scholar 

  52. Ewan, K. B. et al. Proliferation of estrogen receptor-α-positive mammary epithelial cells is restrained by transforming growth factor-β1 in adult mice. Am. J. Pathol. 167, 409–417 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Ciarloni, L., Mallepell, S. & Brisken, C. Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proc. Natl Acad. Sci. USA 104, 5455–5460 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kariagina, A., Xie, J., Leipprandt, J. R. & Haslam, S. Z. Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers. Horm. Cancer 1, 229–244 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Fata, J. E. et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103, 41–50 (2000). This was the first study to identify a role for RANKL in mammary gland development.

    CAS  PubMed  Google Scholar 

  56. Brisken, C. et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 14, 650–654 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Reid, G. et al. Cyclic, proteasome-mediated turnover of unliganded and liganded ERα on responsive promoters is an integral feature of estrogen signaling. Mol. Cell 11, 695–707 (2003).

    CAS  PubMed  Google Scholar 

  58. Sleeman, K. E., Kendrick, H., Ashworth, A., Isacke, C. M. & Smalley, M. J. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res. 8, R7 (2006).

    Google Scholar 

  59. Sleeman, K. E. et al. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. J. Cell Biol. 176, 19–26 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kendrick, H. et al. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 9, 591 (2008).

    PubMed  PubMed Central  Google Scholar 

  61. Oakes, S. R. et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 22, 581–586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  63. Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Farmer, P. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005).

    CAS  PubMed  Google Scholar 

  65. Roy, P. G. et al. High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer. Int. J. Cancer 127, 355–360 (2010).

    CAS  PubMed  Google Scholar 

  66. Kenny, F. S. et al. Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer. Clin. Cancer Res. 5, 2069–2076 (1999).

    CAS  PubMed  Google Scholar 

  67. Rudas, M. et al. Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy. Clin. Cancer Res. 14, 1767–1774 (2008).

    CAS  PubMed  Google Scholar 

  68. Stendahl, M. et al. Cyclin D1 overexpression is a negative predictive factor for tamoxifen response in postmenopausal breast cancer patients. Br. J. Cancer 90, 1942–1948 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Fu, M., Wang, C., Li, Z., Sakamaki, T. & Pestell, R. G. Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 145, 5439–5447 (2004).

    CAS  PubMed  Google Scholar 

  70. Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    CAS  PubMed  Google Scholar 

  71. Cao, Y. et al. IKKα provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107, 763–775 (2001).

    CAS  PubMed  Google Scholar 

  72. Brisken, C. et al. IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev. Cell 3, 877–887 (2002).

    CAS  PubMed  Google Scholar 

  73. Mulac-Jericevic, B., Lydon, J. P., DeMayo, F. J. & Conneely, O. M. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc. Natl Acad. Sci. USA 100, 9744–9749 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Mukherjee, A. et al. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J. 24, 4408–4419 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Joshi, P. A. et al. Progesterone induces adult mammary stem cell expansion. Nature 465, 803–807 (2010).

    CAS  PubMed  Google Scholar 

  76. Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010).

    CAS  PubMed  Google Scholar 

  77. Schramek, D. et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 468, 98–102 (2010). This study provided genetic evidence for a role of RANK signalling in mouse mammary tumorigenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).

    CAS  PubMed  Google Scholar 

  79. van Amerongen, R., Bowman, A. N. & Nusse, R. Developmental stage and time dictate the fate of Wnt/β-catenin-responsive stem cells in the mammary gland. Cell Stem Cell 11, 387–400 (2012).

    CAS  PubMed  Google Scholar 

  80. Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058 (2011).

    PubMed  PubMed Central  Google Scholar 

  81. Ingman, W. V., Wyckoff, J., Gouon-Evans, V., Condeelis, J. & Pollard, J. W. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev. Dyn. 235, 3222–3229 (2006).

    CAS  PubMed  Google Scholar 

  82. Dong, J. et al. ID4 regulates mammary gland development by suppressing p38MAPK activity. Development 138, 5247–5256 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Fernandez-Valdivia, R. et al. Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology 149, 6236–6250 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Aldaz, C. M., Liao, Q. Y., LaBate, M. & Johnston, D. A. Medroxyprogesterone acetate accelerates the development and increases the incidence of mouse mammary tumors induced by dimethylbenzanthracene. Carcinogenesis 17, 2069–2072 (1996).

    CAS  PubMed  Google Scholar 

  85. Gonzalez-Suarez, E. et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 468, 103–107 (2010). This study showed that pharmacological inhibition of RANK signalling in a mouse mammary tumour model slows tumour development.

    CAS  PubMed  Google Scholar 

  86. Gonzalez-Suarez, E. et al. RANK overexpression in transgenic mice with mouse mammary tumor virus promoter-controlled RANK increases proliferation and impairs alveolar differentiation in the mammary epithelia and disrupts lumen formation in cultured epithelial acini. Mol. Cell. Biol. 27, 1442–1454 (2007).

    CAS  PubMed  Google Scholar 

  87. Nusse, R. & Varmus, H. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 31, 99–109 (1982).

    CAS  PubMed  Google Scholar 

  88. Tsukamoto, A., Grosschedl, R., Guzman, R., Parslow, T. & Varmus, H. Expression of the int-1 gene in transgenic mice is associated with mammary gland hyperplasia and adenocarcinomas in male and female mice. Cell 55, 619–625 (1988).

    CAS  PubMed  Google Scholar 

  89. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nature Rev. Cancer 13, 11–26 (2012).

    Google Scholar 

  90. Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Huggins, C., Briziarelli, G. & Sutton, H. Jr. Rapid induction of mammary carcinoma in the rat and the influence of hormones on the tumors. J. Exp. Med. 109, 25–42 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Cheung, S. Y. et al. An expression study of hormone receptors in spontaneously developed, carcinogen-induced and hormone-induced mammary tumors in female Noble rats. Int. J. Oncol. 22, 1383–1395 (2003).

    CAS  PubMed  Google Scholar 

  93. Graham, J. D. et al. Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Mol. Endocrinol. 19, 2713–2735 (2005).

    CAS  PubMed  Google Scholar 

  94. Mulac-Jericevic, B., Mullinax, R. A., DeMayo, F. J., Lydon, J. P. & Conneely, O. M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science 289, 1751–1754 (2000).

    CAS  PubMed  Google Scholar 

  95. Richer, J. K. et al. Differential gene regulation by the two progesterone receptor isoforms in human breast cancer cells. J. Biol. Chem. 277, 5209–5218 (2002).

    CAS  PubMed  Google Scholar 

  96. Aupperlee, M. D., Smith, K. T., Kariagina, A. & Haslam, S. Z. Progesterone receptor isoforms A and B: temporal and spatial differences in expression during murine mammary gland development. Endocrinology 146, 3577–3588 (2005).

    CAS  PubMed  Google Scholar 

  97. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    CAS  PubMed  Google Scholar 

  98. Lee, S. et al. Alterations of gene expression in the development of early hyperplastic precursors of breast cancer. Am. J. Pathol. 171, 252–262 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Palafox, M. et al. RANK induces epithelial-mesenchymal transition and stemness in human mammary epithelial cells and promotes tumorigenesis and metastasis. Cancer Res. 72, 2879–2888 (2012).

    CAS  PubMed  Google Scholar 

  100. Wen, Y. H. et al. Id4 protein is highly expressed in triple-negative breast carcinomas: possible implications for BRCA1 downregulation. Breast Cancer Res. Treat. 135, 93–102 (2012).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The author apologizes for the numerous studies she could not mention because of space constraints, and thanks C. Lebrand, R. Iggo, and M. Fiche for critical reading of the manuscript and valuable suggestions.

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Glossary

17β-oestradiol

The predominant form of oestrogen in the human body it is more abundant than oestrone and oestriol both in terms of serum levels and oestrogenic activity.

Aromatase inhibitors

Drugs that block aromatase, the enzyme that converts androgens to oestrogens in tissues, including the breast and adipose tissue. They are used to treat oestrogen receptor-positive patients with breast cancer by decreasing circulating levels of oestrogenic compounds.

Hormone replacement therapy

(HRT). The administration of hormones to correct a deficiency, such as postmenopausal lack of oestrogen.

Myoepithelial cells and basal cells

The two terms are often used interchangeably, but strictly speaking myoepithelial cells express markers for α-smooth muscle actin (αSMA), caldesmon, p63 and cytokeratin 5 or cytokeratin 6 and other high molecular mass cytokeratins. Basal cells are all the cells that do not touch the lumen hence they include subluminal cells and myoepithelial cells.

Luminal cells

Cells that touch the lumen of the mammary ductal system.

Bromodeoxyuridine

(BrdU). An analogue of thymidine that can be incorporated into the newly synthesized DNA of replicating cells and is used to detect proliferating cells.

Mouse mammary tumour virus

(MMTV). Causes mammary adenocarcinoma in infected mice and selectively replicates in the alveolar epithelial cells of the mammary gland. The MMTV promoter and enhancer are often used to direct the expression of transgenes specifically in the mammary gland.

Selective progesterone receptor modulators

(SPRMs). Similar to SERMs, these compounds can selectively stimulate or inhibit the progesterone receptor in different tissue types.

Selective oestrogen receptor modulators

(SERMs). Compounds (such as tamoxifen and raloxifene) that act on the oestrogen receptor (ER). They can have different effects in different tissues, allowing selective inhibition or stimulation of ER.

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Brisken, C. Progesterone signalling in breast cancer: a neglected hormone coming into the limelight. Nat Rev Cancer 13, 385–396 (2013). https://doi.org/10.1038/nrc3518

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