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Deciphering the divergent roles of progestogens in breast cancer

Nature Reviews Cancer volume 17, pages 54–64 (2017)Cite this article

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Abstract

Most breast cancers are driven by oestrogen receptor-α. Anti-oestrogenic drugs are the standard treatment for these breast cancers; however, treatment resistance is common, necessitating new therapeutic strategies. Recent preclinical and historical clinical studies support the use of progestogens to activate the progesterone receptor (PR) in breast cancers. However, widespread controversy exists regarding the role of progestogens in this disease, hindering the clinical implementation of PR-targeted therapies. Herein, we present and discuss data at the root of this controversy and clarify the confusion and misinterpretations that have consequently arisen. We then present our view on how progestogens may be safely and effectively used in treating breast cancer.

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Figure 1: Comparative anatomy of adult human and mouse mammary gland epithelium.
Figure 2: Endocrine and paracrine interactions in ER+ breast epithelial cell proliferation.
Figure 3: Schematic of PR-mediated reprogramming of ER transcriptional activity.
Figure 4: Hormone receptor status in patients with breast cancer versus models of breast cancer.

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  • 30 November 2016

    In this article, the sentence "The T47D-Y derivatives express substantially lower levels of ER than endogenous T47D cells." on page 8 was incorrectly referenced. The correct references are 119 and 135, not 23 and 135. This has been corrected online.

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Acknowledgements

The authors acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. J.S.C is supported by a European Research Council (ERC) Consolidator grant and a Komen Scholar Award. The work of the authors is supported by funding from the National Health and Medical Research Council of Australia (ID 1008349 to W.D.T. and T.E.H.; ID 1084416 to W.D.T., T.E.H. and J.S.C.); Cancer Australia/National Breast Cancer Foundation of Australia (ID 1043497 to W.D.T., T.E.H. and J.S.C.; ID 1107170 to W.D.T., T.E.H. and J.S.C.); the National Breast Cancer Foundation of Australia (PS-15-041 to W D.T. and G.A.T.); and an unrestricted grant from GTx (W.D.T. and T.E.H.). T.E.H held a Fellowship Award from the US Department of Defense Breast Cancer Research Program (BCRP; #W81XWH-11-1-0592) and currently is supported by a Florey Career Development Fellowship from the Royal Adelaide Hospital Research Foundation.

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Authors and Affiliations

  1. Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK

    Jason S. Carroll

  2. Dame Roma Mitchell Cancer Research Laboratories, Hanson Institute and School of Medicine, University of Adelaide, Adelaide, 5005, SA, Australia

    Theresa E. Hickey, Gerard A. Tarulli & Wayne D. Tilley

  3. Division of Epidemiology, Department of Public Health and Preventive Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, 97239-3098, Oregon, USA

    Michael Williams

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Correspondence to Jason S. Carroll or Wayne D. Tilley.

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Michael Williams has represented women with legal claims for breast cancer induced by medroxyprogesterone acetate or norethindrone acetate when used as menopausal hormone therapy. The other authors declare no potential competing interests.

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Glossary

Aromatase inhibitor

A class of drugs that inhibit the enzyme aromatase (CYP19A1), which converts androgens (testosterone or androstenedione) into oestrogens. By blocking oestrogen synthesis, these compounds inhibit the action of the oestrogen receptor.

Basal cells

Contractile myoepithelial cells that line mammary ducts and possess a reservoir of stem and progenitor cells. Basal cells are thought to function in milk transport at lactation.

ER

In this article, ER specifically refers to oestrogen receptor-α (ERα) There is also an ERβ, which arises from a different gene, but there is considerable controversy regarding the expression and biological role of ERβ in breast cancer. Most of the literature that refers to ER in breast cancer refers to ERα.

Hormone replacement therapy

This therapy (now called menopausal hormone therapy) is used to ameliorate symptoms that arise as a consequence of menopause in which the ovaries are unable to produce sufficient oestrogen and progesterone hormones.

Luminal cells

Secretory cells that reside juxtaposed to basal cells and are composed of two distinct subpopulations: milk-producing alveolar cells and oestrogen receptor (ER)+ and/or progesterone receptor (PR)+ cells. ER+ and PR+ cells respond to endocrine reproductive cues (for example, oestrogen and progesterone) and translate them into paracrine factors that coordinate mammary development during pregnancy.

Micronization

A process by which large particles are broken down into very small particles to increase surface area. In pharmacology, this process can increase the rate of intestinal absorption of oral drugs. Progesterone is one example of a drug that is not well absorbed unless micronized.

Microstructures

A collection of cells that retain anatomical structure that accurately reflects their site of origin.

PR-A and PR-B

The progesterone receptor (PR) exists in two isoforms, PR-A and PR-B, that are produced from the same gene. PR-B has the same protein sequence as PR-A, but with an additional region termed the 'activation function 3′ at the amino terminus of the protein.

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Carroll, J., Hickey, T., Tarulli, G. et al. Deciphering the divergent roles of progestogens in breast cancer. Nat Rev Cancer 17, 54–64 (2017). https://doi.org/10.1038/nrc.2016.116

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