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

被引：48

作者：

Asperger, Hannah ^{[1
]}

Stamm, Nadia ^{[1
]}

Gierke, Berthold ^{[2
]}

Pawlak, Michael ^{[2
]}

Hofmann, Ute ^{[3
,4
]}

Zanger, Ulrich M. ^{[3
,4
]}

Marton, Annamaria ^{[5
]}

Katona, Robert L. ^{[6
]}

Buhala, Andrea ^{[5
]}

Vizler, Csaba ^{[5
]}

Cieslik, Jan-Philipp ^{[1
]}

Ruckhaeberle, Eugen ^{[1
]}

Niederacher, Dieter ^{[1
]}

Fehm, Tanja ^{[1
]}

Neubauer, Hans ^{[1
]}

Ludescher, Marina ^{[1
]}

机构：

[1] Heinrich Heine Univ Duesseldorf, Dept Obstet & Gynecol, Univ Hosp & Med Fac, Life Sci Ctr, Merowingerpl 1A, D-40225 Dusseldorf, Germany

[2] NMI TT Pharmaserv, Prot Profiling, Reutlingen, Germany

[3] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany

[4] Univ Tubingen, Stuttgart, Germany

[5] Biol Res Ctr, Inst Biochem, Szeged, Hungary

[6] Biol Res Ctr, Inst Genet, Szeged, Hungary

来源：

BREAST CANCER RESEARCH | 2020年 / 22卷 / 01期

关键词：

PGRMC1; Breast cancer; Tumor progression; Cholesterol; Lipids; Estrogen receptor alpha; HER2; EGFR; Breast cancer signaling pathway; FATTY-ACID SYNTHASE; PGRMC1; CHOLESTEROL; RAFTS; EXPRESSION; GROWTH; CELLS; METABOLISM; PHENOTYPE; PROGNOSIS;

D O I：

10.1186/s13058-020-01312-8

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 ER alpha 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 ER alpha 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 ER alpha expression and activation, as well as EGFR signaling. Our present study underlines the potential of PGRMC1 as a target for anti-cancer therapy.

引用

页数：16

共 63 条

[1] Statins and breast cancer prognosis: evidence and opportunities [J].