Epigenetic Dysregulation of Imprinting and Triple-Negative Breast Cancer.

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. However, gene amplification accounts for increased expression in <10% of these breast cancers. Here, we showed that is imprinted in breast tissue and identified a differentially methylated region (DMR) controlling its imprint status. Hypomethylation at the DMR, coupled with biallelic expression of , occurred in 63% of triple-negative breast cancers (TNBC). The association between hypomethylation and TNBC status was highly significant in African-Americans ( = 0.006), but not in Caucasians ( = 0.70). hypomethylation was also found in non-cancerous tissue from 77% of women at high-risk of developing breast cancer. Functional studies demonstrated that the gene product, TASK3, regulates mitochondrial membrane potential and apoptosis-sensitivity. In TNBC cells and non-cancerous mammary epithelial cells from high-risk women, hypomethylation of the DMR predicts for increased TASK3 expression and mitochondrial membrane potential ( < 0.001). This is the first identification of the DMR in mammary epithelial cells and demonstration that its hypomethylation in breast cancer is associated with increases in both mitochondrial membrane potential and apoptosis resistance. The high frequency of hypomethylation of the DMR in TNBC and non-cancerous breast tissue from high-risk women provides evidence that hypomethylation of the DMR/TASK3 overexpression may serve as a marker of risk and a target for prevention of TNBC, particularly in African American women.