PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling

In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interactio...

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Autores principales:	Yingxue Bai, Marina Ludescher, Gereon Poschmann, Kai Stühler, Martine Wyrich, Julia Oles, André Franken, Mahdi Rivandi, Anna Abramova, Florian Reinhardt, Eugen Ruckhäberle, Dieter Niederacher, Tanja Fehm, Michael A. Cahill, Nadia Stamm, Hans Neubauer
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	PGRMC1 progesterone progestins breast cancer estrogen receptor hormone therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/6a9e08196bd446198cfebd6c4010e315
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spelling	oai:doaj.org-article:6a9e08196bd446198cfebd6c4010e3152021-11-25T17:01:54ZPGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling10.3390/cancers132256352072-6694https://doaj.org/article/6a9e08196bd446198cfebd6c4010e3152021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5635https://doaj.org/toc/2072-6694In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.Yingxue BaiMarina LudescherGereon PoschmannKai StühlerMartine WyrichJulia OlesAndré FrankenMahdi RivandiAnna AbramovaFlorian ReinhardtEugen RuckhäberleDieter NiederacherTanja FehmMichael A. CahillNadia StammHans NeubauerMDPI AGarticlePGRMC1progesteroneprogestinsbreast cancerestrogen receptorhormone therapyNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5635, p 5635 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	PGRMC1 progesterone progestins breast cancer estrogen receptor hormone therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	PGRMC1 progesterone progestins breast cancer estrogen receptor hormone therapy Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yingxue Bai Marina Ludescher Gereon Poschmann Kai Stühler Martine Wyrich Julia Oles André Franken Mahdi Rivandi Anna Abramova Florian Reinhardt Eugen Ruckhäberle Dieter Niederacher Tanja Fehm Michael A. Cahill Nadia Stamm Hans Neubauer PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
description	In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα). We report that PGRMC1 overexpression resulted in increased proliferation of hormone receptor positive breast cancer cell lines upon treatment with a subgroup of progestins including norethisterone and dydrogesterone that promote PGRMC1-phosphorylation on S181. The ERα modulators prohibitin-1 (PHB1) and prohibitin-2 (PHB2) interact with PGRMC1 in dependency on S181-phosphorylation upon treatment with the same progestins. Moreover, increased interaction between PGRMC1 and PHBs correlated with decreased binding of PHBs to ERα and subsequent ERα activation. Inhibition of either PGRMC1 or ERα abolished this effect. In summary, we provide strong evidence that activated PGRMC1 associates with PHBs, competitively removing them from ERα, which then can develop its transcriptional activities on target genes. This study emphasizes the role of PGRMC1 in a key breast cancer signaling pathway which may provide a new avenue to target hormone-dependent breast cancer.
format	article
author	Yingxue Bai Marina Ludescher Gereon Poschmann Kai Stühler Martine Wyrich Julia Oles André Franken Mahdi Rivandi Anna Abramova Florian Reinhardt Eugen Ruckhäberle Dieter Niederacher Tanja Fehm Michael A. Cahill Nadia Stamm Hans Neubauer
author_facet	Yingxue Bai Marina Ludescher Gereon Poschmann Kai Stühler Martine Wyrich Julia Oles André Franken Mahdi Rivandi Anna Abramova Florian Reinhardt Eugen Ruckhäberle Dieter Niederacher Tanja Fehm Michael A. Cahill Nadia Stamm Hans Neubauer
author_sort	Yingxue Bai
title	PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
title_short	PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
title_full	PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
title_fullStr	PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
title_full_unstemmed	PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling
title_sort	pgrmc1 promotes progestin-dependent proliferation of breast cancer cells by binding prohibitins resulting in activation of erα signaling
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/6a9e08196bd446198cfebd6c4010e315
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PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling

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