VD₃ and LXR agonist (T0901317) combination demonstrated greater potency in inhibiting cholesterol accumulation and inducing apoptosis via ABCA1-CHOP-BCL-2 cascade in MCF-7 breast cancer cells

Obesity is associated with hypercholesterolemia and is a global epidemic. Epidemiological and animal studies revealed cholesterol is an essential regulator of estrogen receptor positive (ER+) breast cancer progression while inhibition of cholesterol accumulation was found to prevent breast tumor growth. Individually, vitamin D and LXR agonist T0901317 showed anticancer properties. The present study investigated the effects of vitamin D₃ (VD₃, calcitriol), LXR agonist (T0901317) and a combination of VD₃ + T0901317 on cholesterol metabolism and cancer progression in ER+ breast cancer (MCF-7) cells. VD₃ or T0901317 alone reduced cholesterol accumulation significantly in MCF-7 cells concomitant with an induction of ABCA1 protein and gene expression compared to the control treatment. Most importantly, VD₃ + T0901317 combination showed higher effects in reducing cholesterol levels and increasing ABCA1 protein and gene expression compared to individual treatments. Importantly, VD₃ + T0901317 combination showed higher effects in increasing apoptosis as measured by annexin apoptosis assay, cell viability and was associated with induction of CHOP protein and gene expression. Additionally, the VD₃ + T0901317 exerted higher effects in reducing antiapoptotic BCL-2 while increased pro-apoptotic BAX gene expression compared to the individual treatments. The present results suggest that VD₃ and T0901317 combination may have an important therapeutic application to prevent obesity and hyperlipidemia mediated ER+ breast cancer progression.