Abstract C65: Loss of imprinting of KCNK9 in African American women with triple-negative breast cancer

Background: It has been long suspected that prenatal nutrition and environmental toxins play a role in promoting 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. Recent studies show that exposure to the environmental plastic bis-phenol A and vitamin D deficiencies promote loss of normal imprinting. African American (AA) women are known to have vitamin D deficiency at a significantly higher frequency than women of Northern European descent. Here we investigated a mechanism that may explain the higher rate of aggressive triple-negative breast cancers (TNBC) in AA women.

Methods and Results: KCNK9 encodes TASK3, a pH-regulated potassium channel membrane protein that is overexpressed in 40% of breast cancer. Our studies have identified a differentially methylated region (DMR) for KCNK9 and shown monoallelic expression of KCNK9 in breast tissue. Using patient samples, we show loss of imprinted expression in tumor cells, loss of KCNK9 regulatory methylation in 75% of TNBC samples, and loss of methylation in non-cancerous tissue from high-risk AA women. In live TNBC cells and non-cancerous mammary epithelial cells from high-risk women, loss of KCNK9 DMR methylation correlates with increased mitochondrial membrane potential.

Significance: This is the first identification of the KCNK9 DMR and demonstration that loss of methylation and overexpression of TASK3 increases mitochondrial membrane potential and promotes apoptosis resistance. These novel findings regarding KCNK9 loss of methylation and its disruption in a subset of tumors may lead to new approaches in diagnosis and targeted therapy of breast cancer.

Citation Format: Shraddha Desai, David Skaar, Eric Dietze, Adrian Ambrose, Randy Jirtle, Victoria Seewaldt. Loss of imprinting of KCNK9 in African American women with triple-negative breast cancer. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C65. doi:10.1158/1538-7755.DISP13-C65