PGRMC1 alters de novo lipid biosynthesis resulting in enhanced oncogenic signaling

Background Progesterone Receptor Membrane Component-1 (PGRMC1) is upregulated in breast cancers and is associated with a worse survival in breast cancer patients. In the present study we describe a potential mechanism by which PGRMC1 potentially contributes to breast cancer progression through deregulation of cholesterol and lipid homeostasis, leading to enhanced oncogenic signaling.

Methods PGRMC1 interaction partners were identified by co-immunoprecipitation followed by mass spectrometry and validated using proximity ligation assay in various breast cancer cell lines. To study how elevated PGRMC1 expression contributes to cholesterol homeostasis, we determined levels of cholesterol and its metabolites in PGRMC1 overexpressing breast cancer cells and investigated sensitivity to statin treatment. Additionally, we determined the activity of estrogen receptor (ERα) at conditions of PGRMC1 overexpression and downregulation.

Results PGRMC1 overexpression resulted in increased proliferation rates in cell culture and in significantly increased tumor volume in xenograft models. PGRMC1 was further found to interact with proteins involved in cholesterol and lipid synthesis. Overexpression of PGRMC1 resulted in increased cholesterol- and estradiol levels, indicating a contribution of PGRMC1 to cholesterol homeostasis. Finally, a positive correlation between PGRMC1 and ERα expression levels and -activation was identified, suggesting the activation of ERα signaling by cholesterol metabolites.

Conclusion PGRMC1 is potentially involved in cholesterol homeostasis by modulation of enzymes of the respective biosynthesis pathway resulting in elevated levels of cholesterol and its metabolites. Subsequent activation of oncogenic signaling cascades could contribute to breast cancer progression. Therefore PGRMC1 represents a potential target for anti-cancer therapy.

Publication History

Article published online:
07 October 2020