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01-12-2020 | Breast Cancer | Research article

Progesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression

Authors: Hannah Asperger, Nadia Stamm, Berthold Gierke, Michael Pawlak, Ute Hofmann, Ulrich M. Zanger, Annamaria Marton, Robert L. Katona, Andrea Buhala, Csaba Vizler, Jan-Philipp Cieslik, Eugen Ruckhäberle, Dieter Niederacher, Tanja Fehm, Hans Neubauer, Marina Ludescher

Published in: Breast Cancer Research | Issue 1/2020

Abstract

Background

PGRMC1 (progesterone receptor membrane component 1) is a highly conserved heme binding protein, which is overexpressed especially in hormone receptor-positive breast cancer and plays an important role in breast carcinogenesis. Nevertheless, little is known about the mechanisms by which PGRMC1 drives tumor progression. The aim of our study was to investigate the involvement of PGRMC1 in cholesterol metabolism to detect new mechanisms by which PGRMC1 can increase lipid metabolism and alter cancer-related signaling pathways leading to breast cancer progression.

Methods

The effect of PGRMC1 overexpression and silencing on cellular proliferation was examined in vitro and in a xenograft mouse model.

Next, we investigated the interaction of PGRMC1 with enzymes involved in the cholesterol synthesis pathway such as CYP51, FDFT1, and SCD1. Further, the impact of PGRMC1 expression on lipid levels and expression of enzymes involved in lipid homeostasis was examined. Additionally, we assessed the role of PGRMC1 in key cancer-related signaling pathways including EGFR/HER2 and ERα signaling.

Results

Overexpression of PGRMC1 resulted in significantly enhanced proliferation. PGRMC1 interacted with key enzymes of the cholesterol synthesis pathway, alters the expression of proteins, and results in increased lipid levels. PGRMC1 also influenced lipid raft formation leading to altered expression of growth receptors in membranes of breast cancer cells. Analysis of activation of proteins revealed facilitated ERα and EGFR activation and downstream signaling dependent on PGRMC1 overexpression in hormone receptor-positive breast cancer cells. Depletion of cholesterol and fatty acids induced by statins reversed this growth benefit.

Conclusion

PGRMC1 may mediate proliferation and progression of breast cancer cells potentially by altering lipid metabolism and by activating key oncogenic signaling pathways, such as ERα expression and activation, as well as EGFR signaling. Our present study underlines the potential of PGRMC1 as a target for anti-cancer therapy.

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Title: Progesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression
Authors: Hannah Asperger
Nadia Stamm
Berthold Gierke
Michael Pawlak
Ute Hofmann
Ulrich M. Zanger
Annamaria Marton
Robert L. Katona
Andrea Buhala
Csaba Vizler
Jan-Philipp Cieslik
Eugen Ruckhäberle
Dieter Niederacher
Tanja Fehm
Hans Neubauer
Marina Ludescher
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Progesterone
Estrogens
Published in: Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-020-01312-8

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