rs10514231 Leads to Breast Cancer Predisposition by Altering ATP6AP1L Gene Expression

SIMPLE SUMMARY: Breast cancer is the most common malignancy in women worldwide. Genome-wide association studies have identified thousands of genetic variants associated with predisposition to breast cancer. It is of vital importance to illustrate the biological mechanisms of these variants in breast cancer progression. Here, we revealed that rs10514231 affects breast cancer risk by altering ATP6AP1L expression through a functional interaction with TCF7L2. Our findings will be valuable for breast cancer risk prediction and effective targeted therapy for cancer patients. ABSTRACT: 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 ATG10 and showed gene regulatory activity in most breast cancer cells we used. Mechanistically, the T allele of rs10514231 led to ATP6AP1L downregulation by decreasing the binding affinity of TCF7L2. Overexpression of the ATP6AP1L gene in cancer cells diminished cell proliferation, migration, and invasion. Notably, ATP6AP1L 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.