Progesterone receptor isoform ratios influence the transcriptional activity of progestins via the progesterone receptor.

Meghan Cartwright, Renate Louw-du Toit, Hayley Jackson, Melani Janse van Vuuren, Donita Africander

The Journal of steroid biochemistry and molecular biology 2023 Sep

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Progestins (synthetic progestogens) are progesterone receptor (PR) ligands used globally by women in both hormonal contraception and menopausal hormone therapy. Although four generations of unique progestins have been developed, studies seldom distinguish between the activities of progestins via the two functionally distinct PR isoforms, PR-A and PR-B. Moreover, not much is known about the action of progestins in breast cancer tumors where PR-A is mostly overexpressed relative to PR-B. Understanding progestin action in breast cancer is crucial since the clinical use of some progestins has been associated with an increased risk of developing breast cancer. This study directly compared the agonist activities of selected progestins from all four generations for transactivation and transrepression via either PR-A or PR-B, and when PR-A and PR-B were co-expressed at ratios comparable to those detected in breast cancer tumors. Comparative dose-response analysis showed that earlier generation progestins mostly displayed similar efficacies for transactivation on a minimal progesterone response element via the PR isoforms, while most of the 4th generation progestins, similar to the natural progestogen, progesterone (P4), were more efficacious via PR-B. Most of the progestogens were however more potent via PR-A. We are the first to show that the efficacies of the selected progestogens via the individual PR isoforms were generally decreased when PR-A and PR-B were co-expressed, irrespective of the ratio of PR-A:PR-B. While the potencies of most progestogens via PR-B were enhanced when the ratio of PR-A relative to PR-B was increased, those via PR-A were minimally influenced. This study is also the first to report that all progestogens evaluated, except 1st generation medroxyprogesterone acetate and 4th generation drospirenone, displayed similar agonist activity for transrepression via PR-A and PR-B on a minimal nuclear factor kappa B containing promoter. Moreover, we showed that the progestogen activity for transrepression was significantly increased when PR-A and PR-B were co-expressed. Taken together, our results highlight that PR agonists (progestogens) do not always display the same activity via PR-A and PR-B, or when PR-A and PR-B are co-expressed at ratios mimicking those found in breast cancer tumors. These results suggest that biological responses are progestogen- and PR isoform-dependent and may differ in target tissues expressing varying PR-A:PR-B ratios. Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

Citation

Meghan Cartwright, Renate Louw-du Toit, Hayley Jackson, Melani Janse van Vuuren, Donita Africander. Progesterone receptor isoform ratios influence the transcriptional activity of progestins via the progesterone receptor. The Journal of steroid biochemistry and molecular biology. 2023 Sep;232:106348