Abstract
BackgroundPGRMC1 (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.MethodsThe 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.ResultsOverexpression 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.ConclusionPGRMC1 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.
Highlights
Progesterone receptor membrane component 1 (PGRMC1) 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
To further strengthen our theory, we examined the impact of PGRMC1 silencing on tumor proliferation by knocking down endogenous PGRMC1 expression
Cholesterol and fatty acid depletion induced by statins reverses the growth benefit interceded by PGRMC1 Our findings suggest a complex and broad role of PGRMC1 in cholesterol and lipid metabolism (Fig. 5d)
Summary
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. 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. Many studies describe an association of high plasma and endogenous cholesterol levels with (breast) cancer development and progression [19,20,21], pointing towards a major role in cancer. Elevated cholesterol and steroid levels may affect carcinogenesis in different ways, e.g., in saturating the increased requirement for membrane components due to abundant cell growth [22]. Cholesterol is the precursor of steroid hormones like estradiol (E2), the important growth factor for hormone receptor-positive breast cancer [26]
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