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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).
Banerji, S. et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 486, 405–409 (2012).
Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nature Rev. Cancer 12, 323–334 (2012).
Almendro, V., Marusyk, A. & Polyak, K. Cellular heterogeneity and molecular evolution in cancer. Annu. Rev. Pathol. 8, 277–302 (2012).
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.
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).
Nandi, S. Endocrine control of mammary-gland development in the C3H/He Crgl mouse. J. Natl Cancer Inst. 21, 1039–1063 (1958).
Lyons, W. R. Hormonal synergism in mammary growth. Proc. R. Soc. Lond. B Biol. Sci. 149, 303–325 (1958).
MacMahon, B. et al. Age at first birth and breast cancer risk. Bull. World Health Organ. 43, 209–221 (1970).
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).
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'.
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).
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).
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).
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).
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).
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).
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).
Beral, V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362, 419–427 (2003).
Chlebowski, R. T. et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304, 1684–1692 (2010).
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).
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).
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).
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).
Sitruk-Ware, R. Pharmacological profile of progestins. Maturitas 47, 277–283 (2004).
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).
Chlebowski, R. T. et al. Breast cancer after use of estrogen plus progestin in postmenopausal women. N. Engl. J. Med. 360, 573–587 (2009).
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).
Boyd, N. F. et al. Mammographic density and the risk and detection of breast cancer. N. Engl. J. Med. 356, 227–236 (2007).
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).
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).
Greendale, G. A. et al. Postmenopausal hormone therapy and change in mammographic density. J. Natl Cancer Inst. 95, 30–37 (2003).
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).
Beleut, M. et al. Two distinct mechanisms underlie progesterone-induced proliferation in the mammary gland. Proc. Natl Acad. Sci. USA 107, 2989–2994 (2010).
Wang, S., Counterman, L. J. & Haslam, S. Z. Progesterone action in normal mouse mammary gland. Endocrinology 127, 2183–2189 (1990).
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).
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).
Lydon, J. et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9, 2266–2278 (1995).
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).
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).
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.
Brisken, C. & O'Malley, B. Hormone action in the mammary gland. Cold Spring Harb. Perspect. Biol. 2, a003178 (2011).
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).
Caligioni, C. S. Assessing reproductive status/stages in mice. Curr. Protoc. Neurosci. 4, Appendix 4I (2009).
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).
Tanos, T. et al. Progesterone/RANKL is a major regulatory axis in the human breast. Sci. Transl. Med. 5, 182ra55 (2013).
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.
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).
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).
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).
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).
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).
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).
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.
Brisken, C. et al. Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling. Genes Dev 14, 650–654 (2000).
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).
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).
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).
Kendrick, H. et al. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 9, 591 (2008).
Oakes, S. R. et al. The Ets transcription factor Elf5 specifies mammary alveolar cell fate. Genes Dev. 22, 581–586 (2008).
Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).
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).
Farmer, P. et al. Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24, 4660–4671 (2005).
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).
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).
Rudas, M. et al. Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy. Clin. Cancer Res. 14, 1767–1774 (2008).
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).
Fu, M., Wang, C., Li, Z., Sakamaki, T. & Pestell, R. G. Minireview: Cyclin D1: normal and abnormal functions. Endocrinology 145, 5439–5447 (2004).
Kong, Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).
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).
Brisken, C. et al. IGF-2 is a mediator of prolactin-induced morphogenesis in the breast. Dev. Cell 3, 877–887 (2002).
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).
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).
Joshi, P. A. et al. Progesterone induces adult mammary stem cell expansion. Nature 465, 803–807 (2010).
Asselin-Labat, M. L. et al. Control of mammary stem cell function by steroid hormone signalling. Nature 465, 798–802 (2010).
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.
Van Keymeulen, A. et al. Distinct stem cells contribute to mammary gland development and maintenance. Nature 479, 189–193 (2011).
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).
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).
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).
Dong, J. et al. ID4 regulates mammary gland development by suppressing p38MAPK activity. Development 138, 5247–5256 (2011).
Fernandez-Valdivia, R. et al. Transcriptional response of the murine mammary gland to acute progesterone exposure. Endocrinology 149, 6236–6250 (2008).
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).
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.
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).
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).
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).
Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nature Rev. Cancer 13, 11–26 (2012).
Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).
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).
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).
Graham, J. D. et al. Altered progesterone receptor isoform expression remodels progestin responsiveness of breast cancer cells. Mol. Endocrinol. 19, 2713–2735 (2005).
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).
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).
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).
Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).
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).
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).
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).
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.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
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.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrc3518
This article is cited by
-
Novel biosensor for high-throughput detection of progesterone receptor-interacting endocrine disruptors
Scientific Reports (2024)
-
StackPR is a new computational approach for large-scale identification of progesterone receptor antagonists using the stacking strategy
Scientific Reports (2022)
-
Progesterone receptor antagonists reverse stem cell expansion and the paracrine effectors of progesterone action in the mouse mammary gland
Breast Cancer Research (2021)
-
Estrogen receptor-α signaling in post-natal mammary development and breast cancers
Cellular and Molecular Life Sciences (2021)
-
Discordance in 21-gene recurrence scores between paired breast cancer samples is inversely associated with patient age
Breast Cancer Research (2020)