PGRMC1 interacts with proteins of the cholesterol synthesis pathway resulting in altered cholesterol metabolism in breast cancer cells

Background:

Progesterone Receptor Membrane Component-1 (PGRMC1) is upregulated in breast tumors and elevated expression of PGRMC1 is associated with increased tumor growth, suggesting a contribution of PGRMC1 on carcinogenesis of breast cancer. However, the mechanism by which PGRMC1 contributes to breast cancer progression is not understood yet. Here we describe a potential mechanism by which PGRMC1 contributes to progression of breast cancer via deregulation of cholesterol synthesis and metabolization.

Methods:

PGRMC1 interaction partners were identified by co-immunoprecipitation followed by mass spectrometry and validated using proximity ligation assay (PLA) in various breast cancer cell lines. To study how elevated PGRMC1 expression contributes to cholesterol balance, we generated PGRMC1 overexpressing breast cancer cells and determined levels of cholesterol-, lathosterol- and the cholesterol metabolite 27-hydroxycholesterol. Since 27-hydroxycholesterol is presumed to have estrogenic action, stimulating the growth of ER-positive breast cancer cells and limiting the effectiveness of aromatase inhibitors, we further investigated the activity of ERα in PGRMC1 overexpressing cell lines.

Results:

Interaction of PGRMC1 with proteins involved in cholesterol synthesis, including Acyl-CoA desaturase (SCD), Squalene synthase (FDFT1) and Lanosterol 14-alpha demethylase (CYP51A1), was detected by mass spectrometry and verified by PLA. Elevated levels of cholesterol and its metabolites were detected in PGRMC1 overexpressing cells, suggesting a contribution of PGRMC1 to cholesterol synthesis and metabolization. Further, increased activity of ERα was detected in PGRMC1 overexpressing cells, indicating activation of the receptor by cholesterol metabolites.

Conclusion:

Cholesterol metabolism is involved in cancer cell proliferation as well as resistance to anti-cancer therapy. Our results indicate that elevated cholesterol metabolism induced by interaction of PGRMC1 with enzymes of the cholesterol biosynthesis pathway might contribute to malignant transformation and promote breast cancer progression. PGRMC1 might therefore present an interesting target for anti-cancer therapy.