Abstract PR11: Loss of imprinting: Tying prenatal diet to the aggressive biology of triple-negative breast cancer

Background: Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. Loss of normal imprinting results in a functional diploid state and overexpression of the imprinted gene. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancers; however, KCNK9 gene amplification accounts for increased expression in <10% of these breast cancers.

Methods and Results: Using patient samples we showed that KCNK9 has imprinted expression in breast tissue, and identified the differentially methylated region (DMR) controlling its imprint status. We showed that loss of methylation (LOM) at the DMR, coupled with biallelic expression of KCNK9, occurred in 75% of triple-negative breast cancers (TNBC), and that association between LOM and TNBC status was highly significant in African-Americans, but not in Caucasians. Functional studies show that loss of KCNK9 imprinting leads to an increase in mitochondrial membrane potential and apoptosis resistance. Further, expression of a dominant-negative TASK3 in TASK3-overexpressing TNBC cells resulted in decreased mitochondrial membrane potential, decreased glucose uptake and apoptosis-sensitivity; conversely, overexpression of TASK3 in mammary epithelial cells with baseline TASK3 protein expression, increased mitochondrial membrane potential, increased glucose uptake and promoted apoptosis-resistance.

Significance: This is the first identification of the KCNK9 DMR, and demonstration that its LOM is associated with increases in mitochondrial membrane potential, glucose uptake and apoptosis resistance. Thus, patients with TNBC and KCNK9 overexpression may benefit from known low toxicity TASK3 inhibitors for the prevention and treatment of breast cancer.

This abstract was also presented as Poster A79.

Citation Format: Shraddha R. Desai, Eric C. Dietze, David Skaar, Randy L. Jirtle, Victoria L. Seewaldt. Loss of imprinting: Tying prenatal diet to the aggressive biology of triple-negative breast cancer. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr PR11.