Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation. Issue 7 (27th May 2021)

• Record Type: Journal Article
• Authors: Shamseddin, Marie; De Martino, Fabio; Constantin, Céline; Scabia, Valentina; Lancelot, Anne‐Sophie; Laszlo, Csaba; Ayyannan, Ayyakkannu; Battista, Laura; Raffoul, Wassim; Gailloud‐Matthieu, Marie‐Christine; Bucher, Philipp; Fiche, Maryse; Ambrosini, Giovanna; Sflomos, George; Brisken, Cathrin
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 7(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-05-27
• Subjects: androgen receptor signaling -- breast cancer -- hormonal contraception -- progestins -- xenografts; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202114314
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone‐related progestins induce the PR target and mediator of PR signaling‐induced cell proliferation receptor activator of NF‐κB ligand (Rankl), whereas progestins with anti‐androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone‐responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti‐androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist‐ and levonorgestrel‐induced RANKL expression and reduces levonorgestrel‐driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception. Synopsis: Hormonal contraception exposes women to different progestins in conjunction or without estrogen. The androgenic properties of progestins determine their biological activity in the breast epithelium and reveal an unexpected role for AR activity in breast epithelial cell proliferation. Androgenic progestins induce expression of Rankl, an important mediator of PR signaling‐induced cell proliferation in the mammary epithelium, whereas anti‐androgenic progestins fail to do so. AR activity is required for the induction of Rankl transcripts. Human breast epithelial cells engraft and proliferate in mouse milk ducts maintaining nuclear hormone receptor expression and hormone responsiveness. Androgenic but not anti‐androgenic progestins promote cell proliferation in xenografted human breast epithelia. Prolonged exposure to androgenic progestins causes hyperproliferation and cytological changes associated with early premalignant lesions in xenografted human breast epithelia. Abstract : Hormonal contraception exposes women to different progestins in conjunction or without estrogen. The androgenic properties of progestins determine their biological activity in the breast epithelium and reveal an unexpected role for AR activity in breast epithelial cell proliferation.