Open AccessContraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation
Author(s) -
Shamseddin Marie,
De Martino Fabio,
Constantin Céline,
Scabia Valentina,
Lancelot AnneSophie,
Laszlo Csaba,
Ayyannan Ayyakkannu,
Battista Laura,
Raffoul Wassim,
GailloudMatthieu MarieChristine,
Bucher Philipp,
Fiche Maryse,
Ambrosini Giovanna,
Sflomos George,
Brisken Cathrin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114314
Subject(s) - gestodene , progesterone receptor , endocrinology , cyproterone acetate , medicine , levonorgestrel , desogestrel , estrogen , estrogen receptor , biology , cancer research , breast cancer , androgen , hormone , population , cancer , environmental health , family planning , research methodology
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.