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KCNK9 Loss of Imprinting in Triple Negative Breast Cancer

7 January 2022: We previously predicted and experimentally demonstrated that KCNK9 is imprinted in humans, and maternally expressed in the brain (Luedi et al, 2007). We now show that KCNK9 is also expressed only from the maternal allele in breast epithelium, and that loss of imprinting at this locus is linked to the pathogenesis of triple negative breast cancer (TNBC) (Skaar et al, 2021).

Genomic imprinting is an inherited form of parent-of-origin specific epigenetic gene regulation that is dysregulated by poor prenatal nutrition and environmental toxins. KCNK9 encodes for TASK3, a pH-regulated potassium channel membrane protein. It is overexpressed in 40% of breast cancer; however, gene amplification accounts for increased expression in less than 10% of these cancers.

We have now identified a differentially methylated region (DMR) associated with KCNK9 imprinting. Hypomethylation of this DMR is coupled with biallelic expression of KCNK9 and TASK3 overexpression in 63% of TNBC. This association is highly significant in African-Americans (p = 0.006), but not in Caucasians (p = 0.70). KCNK9 hypomethylation is also present in the non-cancerous breast epithelium in 77% of women at high-risk of developing breast cancer. Furthermore, hypomethylation of the KCNK9 DMR enhances mitochondrial membrane potential and apoptosis resistance. Thus, KCNK9 loss of imprinting in TNBC may provide a novel epigenetic target for the diagnosis, prevention, and treatment of TNBC, particularly in African-Americans.