SR-B1 gene variants, inhibitors and the effect of glucose on IC50s in breast cancer

Background: Ancestry-related genetic variations have been observed to influence the risk of certain cancers and diabetes through inherited genetic variations and their interaction with lifestyle and environment. Type 2 diabetes has been considered a risk factor for breast cancer, thus suggesting metabolism may drive cancer progression. The reverse cholesterol transporter and membrane receptor Scavenger receptor B1 (SR-B1), which is involved in insulin resistance and lipid metabolism, with its ancestry enriched variants, is evaluated in breast cancer as a novel target. Methods: The triple negative breast cancer cell lines MDA.MB 231 and MDA.MB 468 were employed for this study. SNP genotyping to determine the genotype of each cell line was performed using the TaqMan SNP Genotyping assays for the SR-B1 missense SNP variant rs2293440. Cells were grown in media with varying glucose levels of 5.5 mM, 17.5 mM and 25 mM, representative of the blood glucose level indicator HbA1C. The cells were then treated with different concentrations of the SR-B1 inhibitor drug, Block lipid transport 1 (BLT-1), for total of 48 hours. After 48 hours, cell survivability assay was used to determine percent survival for each cell line under the conditions mentioned. Results: The SNP genotyping results indicated that MDA.MB 231 contained the wild-type allele while MDA.MB 468 contained the variant allele. Results of the cell survivability assay showed that sensitivity of both the cell lines to BLT-1 was increased by 3-fold and 5-fold at 5.5 mM glucose concentration in media for MDA.MB 231 and 468 respectively, as was confirmed by the IC50 values. Both cell lines displayed resistance to BLT-1 at the higher media glucose concentrations of 17.5 and 25 mM with their IC50 values exhibiting up to a 5-fold increase. Further, MDA.MB 468 displayed almost 2-fold higher sensitivity to BLT-1 at both 5.5 mM and 17.5 mM media glucose concentration in comparison to MDA.MB 231. Conclusions: These results indicate that there is a correlation between the blood glucose levels and the drug sensitivity or drug response in cancer. Further, our results suggest that the response to metabolism inhibitor drugs in cancer and glucose metabolism may also be impacted by the ancestry and genetic variation of an individual.