Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation
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 t...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114314 |
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| author | Marie Shamseddin Fabio De Martino Céline Constantin Valentina Scabia Anne‐Sophie Lancelot Csaba Laszlo Ayyakkannu Ayyannan Laura Battista Wassim Raffoul Marie‐Christine Gailloud‐Matthieu Philipp Bucher Maryse Fiche Giovanna Ambrosini George Sflomos Cathrin Brisken |
| author_facet | Marie Shamseddin Fabio De Martino Céline Constantin Valentina Scabia Anne‐Sophie Lancelot Csaba Laszlo Ayyakkannu Ayyannan Laura Battista Wassim Raffoul Marie‐Christine Gailloud‐Matthieu Philipp Bucher Maryse Fiche Giovanna Ambrosini George Sflomos Cathrin Brisken |
| author_sort | Marie Shamseddin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bb98fa0045ae44db9e9905a05fa2273f |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-bb98fa0045ae44db9e9905a05fa2273f2025-08-20T02:11:29ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-05-0113711910.15252/emmm.202114314Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferationMarie Shamseddin0Fabio De Martino1Céline Constantin2Valentina Scabia3Anne‐Sophie Lancelot4Csaba Laszlo5Ayyakkannu Ayyannan6Laura Battista7Wassim Raffoul8Marie‐Christine Gailloud‐Matthieu9Philipp Bucher10Maryse Fiche11Giovanna Ambrosini12George Sflomos13Cathrin Brisken14Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneCentre Hospitalier Universitaire Vaudois, University Hospital of LausanneInternational Cancer Prevention InstituteSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneInternational Cancer Prevention InstituteSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneSwiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de LausanneAbstract 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.https://doi.org/10.15252/emmm.202114314androgen receptor signalingbreast cancerhormonal contraceptionprogestinsxenografts |
| spellingShingle | Marie Shamseddin Fabio De Martino Céline Constantin Valentina Scabia Anne‐Sophie Lancelot Csaba Laszlo Ayyakkannu Ayyannan Laura Battista Wassim Raffoul Marie‐Christine Gailloud‐Matthieu Philipp Bucher Maryse Fiche Giovanna Ambrosini George Sflomos Cathrin Brisken Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation EMBO Molecular Medicine androgen receptor signaling breast cancer hormonal contraception progestins xenografts |
| title | Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| title_full | Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| title_fullStr | Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| title_full_unstemmed | Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| title_short | Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| title_sort | contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation |
| topic | androgen receptor signaling breast cancer hormonal contraception progestins xenografts |
| url | https://doi.org/10.15252/emmm.202114314 |
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