PGRMC1 alters lipid metabolism – impact on breast cancer progression

Aim:

PGRMC1 (progesterone receptor membrane component 1) is a multifunctional protein associated with tumor progression and a worse outcome. As already shown, PGRMC1 interacts with enzymes of the cholesterol/lipid synthesis and might contribute to tumor growth via a deregulated lipid metabolism. Therefore, the aim of the present study was to investigate the effects of those interactions on a modified lipid metabolism and associated enhanced ERα and HER2 signaling.

Material:

To obtain PGRMC1 overexpressing cell lines, MCF7, T47D and MDA cells were stably transfected with expression plasmid pcDNA3.1. containing HA-tagged PGRMC1. As a control, cells transfected with the empty plasmid were used.

Methods:

Cholesterol and estradiol levels were measured with mass spectrometry and ELISA. Neutral lipids were stained with bodipy and quantified through FACS. Furthermore, lipid rafts were detected using the Vybrant™ Lipid Raft Labeling Kit and analyzed by FACS and immune fluorescence. HER2 expression was determined by western blot and FACS. The impact of lipid inhibition on tumor progression was analyzed by viability assays.

Results:

PGRMC1 overexpression resulted in increased levels of neutral lipids, cholesterol and estradiol in hormone receptor positive breast cancer cells. Additionally, PGRMC1 overexpressing cells show more lipid rafts and higher HER2 expression levels.

Interestingly, PGRMC1 overexpressing cells react more sensitive to a simvastatin treatment, which indicates a higher dependence of PGRMC1 overexpressing cells on cholesterol.

Summary:

PGRMC1 increases lipid metabolism and leads to more lipid raft formation and an enhanced HER2 expression. Hence, PGRMC1 overexpressing tumors could be particularly suitable for a treatment with cholesterol inhibitors.