Progesterone and Breast Cancer
Clinicians have long observed that breast cancer patients who are both estrogen receptor (ER) positive and progesterone receptor (PR) positive have better clinical outcomes. These patients tend to respond better to treatment and have a lower risk of relapse, even though they are treated with the same hormone therapy as their ER-positive, PR-negative counterparts.
There is compelling evidence that inclusion of a progestogen as part of hormone replacement therapy increases the risk of breast cancer, implying that PR signalling can contribute towards tumour formation1. However, the increased risk of breast cancer associated with progestogen-containing hormone replacement therapy is mainly attributed to specific synthetic progestins, in particular medroxyprogesterone acetate (MPA), which is known to also have androgenic properties2. The relative risk is not significant when physiologic progesterone (P4) is used3. In ER alpha+ breast cancers, PR is often used as a positive prognostic marker of disease outcome4, but the functional role of PR signalling remains unclear. While activation of PR may promote breast cancer in some women and in some model systems, progesterone treatment has been shown to be antiproliferative in ER alpha +PR+breast cancer cell lines5–7, and progestogens have been shown to oppose oestrogen-stimulated growth of an ER alpha +PR+ patient-derived xenograft8. In addition, exogenous expression of PR in ER alpha +breast cancer cells blocks estrogen-mediated proliferation and ER alpha transcriptional activity9. Furthermore, in ER alpha +breast cancer patients, PR is an independent predictor of response to adjuvant tamoxifen10, high levels of PR correlate with decreased metastatic events in early stage disease11, and administration of a progesterone injection before surgery can provide improved clinical benefit12. These observations simply that PR activation in the context of oestrogen-driven, ER alpha+ breast cancer, can have an anti-tumorigenic effect. In support of this, PR agonists can exert clinical benefit in ER alpha+ breast cancer patients that have relapsed on ER alpha antagonists13
Recently, Researchers from the United Kingdom and Australia have uncovered the molecular underpinnings of why upregulation of both hormone receptors results in better tumor control. Their results, published in Nature, suggest that hormone therapy with progesterone could be used in the treatment of ER-positive, PR-positive disease, which makes up about half of all diagnosed breast cancers.14
Using ER-positive, PR-positive cell-line xenografts, as well as primary ER-positive breast tumor cells excised from patients and grown in a lab, Jason S. Carroll, PhD, of the Cancer Research UK Cambridge Institute, and colleagues observed that the receptors for estrogen and progesterone physically interacted within the cell. They also found that the global gene expression profile of these cells was different when the cells were exposed to estrogen alone vs estrogen plus progesterone and, in the presence of both hormones, was linked to better clinical outcomes. Adding progesterone to tamoxifen, the researchers found that the ER is redirected to different transcriptional targets, and its activity./
Moreover, the use of progesterone with tamoxifen slowed tumor growth compared with either hormone alone in both cells grown in the lab and in breast cancer tumors implanted into mice.14
While this research is promising use of progesterone (P4) is limited because it is extensively metabolized and has a terminal half-life of approximately 5 minutes in the circulation.
The use of synthetic progestins may not be appropriate, the synthetic progestins used so far for contraception and menopausal hormone therapy are derived either from testosterone (19-nortestosterone derivatives) or from progesterone (17-OH progesterone derivatives and 19-norprogesterone derivatives). Among the 19-nortestosterone derivatives, the estrane group include norethisterone (NET) and its metabolites, and the gonane group include levonorgestrel (LNG) and its derivatives. The later, including desogestrel (DSG) and its derivative etonogestrel, gestodene (GES) and norgestimate (norelgestromin), have been referred to as third-generation progestins. Several newprogestins have been synthesized in the last decade and may be considered as a fourth-generation of progestins. Dienogest is referred to as a hybrid progestin being derived from the estrane group with a 17α-cyanomethyl group, and drospirenone derives from spirolactone. These two progestins have no androgenic effect but a partial antiandrogenic effect. While their action on the endometrium is comparable to progesterone (P4) action at other sites is markedly different from the physiologic hormone.
For example, natural Progesterone, but Not Medroxyprogesterone Acetate, Enhances the Beneficial Effect of Estrogen on Exercise-Induced Myocardial Ischemia in Postmenopausal Women.15
- Chlebowski, R. T. et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. J. Am. Med. Assoc. 304, 1684–1692 (2010).
- Bentel, J. M. et al. Androgen receptor agonist activity of the synthetic progestin, medroxyprogesterone acetate, in human breast cancer cells. Mol. Cell. Endocrinol.154, 11–20 (1999).
- Fournier, A., Berrino, F. & Clavel-Chapelon, F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3Ncohort study. Breast Cancer Res. Treat. 107, 103–111 (2008).
- Blows, F. M. et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 7,e 1000279 (2010).
- Vignon, F., Bardon, S., Chalbos, D. & Rochefort, H. Antiestrogenic effect of R5020, a synthetic progestin in human breast cancer cells in culture. J. Clin. Endocrinol. Metab. 56, 1124–1130 (1983).
- Musgrove, E. A., Swarbrick, A., Lee, C. S., Cornish, A. L. & Sutherland, R. L. Mechanisms of cyclin-dependent kinase inactivation by progestins. Mol. Cell. Biol.18, 1812–1825 (1998).
- Chen, C. C., Hardy, D. B. & Mendelson, C. R. Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1(MKP-1/DUSP1). J. Biol. Chem. 286, 43091–43102 (2011).
- Kabos, P. et al. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen-dependent gene signatures. Breast Cancer Res. Treat. 135, 415–432 (2012).
- Zheng, Z. Y., Bay, B. H., Aw, S. E. & Lin, V. C. A novel antiestrogenic mechanism in progesterone receptor-transfected breast cancer cells. J. Biol. Chem. 280,17480–17487 (2005).
- Bardou, V. J., Arpino, G., Elledge, R. M., Osborne, C. K. & Clark, G. M. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer data bases. J. Clin. Oncol. 21, 1973–1979 (2003).
- Piton, M. F., Palled, C., Brunet, M. & Milgram, E. Relationship of presence of progesterone receptors to prognosis in early breast cancer. Cancer Res. 40,3357–3360 (1980).
- Badwe, R. et al. Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. J. Clin. Oncol.29, 2845–2851 (2011).
- Bines, J. et al. Activity of megestrol acetate in postmenopausal women with advanced breast cancer after nonsteroidal aromatase inhibitor failure: a phase II trial. Ann. Oncol. 25, 831–836 (2014)
- Mohammed H, Russell I.A, Stark R, Rueda O.M, Hickey T.E, Tarulli G.A, Serandour A.A, Birrell S.N, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj G.V, Brown G.D, D’Santos C, Robinson J.L, Silva G, Launchbury R, Perou C.M, Stingl J, Caldas C, Tilley W.D, Carroll J.S.“Progesterone receptor modulates ERα action in breast cancer.”Nature. (2015 Jul 8).
- Giuseppe M. C. Rosano, MD, FACC,* Carolyn M. Webb, PHD,† Sergio Chierchia, MD, FACC,* Gian Luigi Morgani, MD,* Michele Gabraele, MD,* Phillip M. Sarrel, MD,‡ Dominique de Ziegler, MD,§ Peter Collins, MD, FACC† Journal of the American College of Cardiology Vol. 36, No. 7, 2000 ISSN 0735-1097/00/$20.00 PII S0735-1097(00)01007-X