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

Breast Cancer Research

卷:22

Hannah Asperger¹  Hans Neubauer¹  Jan-Philipp Cieslik¹  Tanja Fehm¹  Marina Ludescher¹  Nadia Stamm¹  Eugen Ruckhäberle¹  Dieter Niederacher¹  Ulrich M. Zanger²  Ute Hofmann²  Annamaria Marton³  Andrea Buhala³  Csaba Vizler³  Robert L. Katona⁴  Berthold Gierke⁵  Michael Pawlak⁵ 

[1] Department of Obstetrics and Gynecology, University Hospital and Medical Faculty of the Heinrich-Heine University Duesseldorf, Life Science Center;

[2] Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen;

[3] Institute of Biochemistry, Biological Research Centre;

[4] Institute of Genetics, Biological Research Centre;

[5] NMI TT Pharmaservices, Protein Profiling;

关键词: PGRMC1;    Breast cancer;    Tumor progression;    Cholesterol;    Lipids;    Estrogen receptor α;   

DOI  :  10.1186/s13058-020-01312-8

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown