rs10514231 Leads to Breast Cancer Predisposition by Altering Gene Expression.

Numerous genetic variants located in autophagy-related genes have been identified for association with various cancer risks, but the biological mechanisms underlying these associations remain largely unknown. Here we investigated their regulatory activity with a parallel reporter gene assay system in breast cancer cells and identified multiple regulatory SNP sites, including rs10514231. It was located in the second intron of and showed gene regulatory activity in most breast cancer cells we used. Mechanistically, the T allele of rs10514231 led to downregulation by decreasing the binding affinity of TCF7L2. Overexpression of the gene in cancer cells diminished cell proliferation, migration, and invasion. Notably, downregulation correlated with breast cancer risk and with poor prognosis in patients. These results provide a plausible mechanism behind the association of rs10514231 with breast cancer risk and will be important for more effective therapeutic target identification for precision medicine.