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

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.

Absence of progesterone receptor membrane component 1 reduces migration and metastasis of breast cancer

“…Considering that PGRMC1 was shown to be correlated with the ER status in breast cancer [ 11 ], PGRMC1 may have a role in the regulation of the progression of luminal A and luminal B subtypes of breast cancer. In a previous study using xenograft models, PGRMC1 depletion in MCF7 and T47D cells resulted in suppression of tumor growth [ 12 ]; as both MCF7 and T47D cells belong to the luminal A subtype, PGRMC1 was suggested to regulate the growth of breast cancer via ER signaling [ 12 ]. In the present study, Pgrmc1 KO mice showed a slight decrease in tumor development along with a decrease in the expression of PR.…”

“…Furthermore, considering that Pgrmc1 expression is associated with ERa expression, suppression of Pgrmc1 has been considered as a potential therapeutic approach against the progression of breast cancer [ 11 ]. As Pgrmc1 is involved in estrogen synthesis, a recent study showed that a high level of Pgrmc1 promotes the development of breast cancer in a xenograft model [ 12 ]. Moreover, another study also reported that Pgrmc1 is involved in mTOR activation and EGFR signaling [ 13 ].…”

PGRMC1 Inhibits Progesterone-Evoked Proliferation and Ca2+ Entry Via STIM2 in MDA-MB-231 Cells

“…PGRMC1 expression is enhanced in patients suffering from different types of tumors, resulting in poor prognosis [ 12 , 13 ]. In line with this observation, PGRMC1 has been linked with lipid metabolism, which would lead to enhanced breast cancer progression [ 14 , 15 ]. It is worth mentioning that the role of PGRMC1 is mainly evidenced in the luminal type A breast cancer cell lines (MCF7 and T47-D); meanwhile, MDA-MB-231 cell proliferation remains unaltered, even when PGRMC1 expression is artificially altered [ 14 ].…”

PGRMC Proteins Are Coming of Age: A Special Issue on the Role of PGRMC1 and PGRMC2 in Metabolism and Cancer Biology

“…These numbers not only indicate the current focus of the ‘PGRMC-research’, but also reflect a substantive connection between these fields. Metabolic changes such as alterations in lipid- and cholesterol-associated pathways mediated by PGRMCs not only enhance obesity [ 12 ], but are also a recognized hallmark of cancer (cancer-associated metabolic programming) [ 13 ] associated with potential therapy resistance mechanisms [ 14 ].…”