Abstract 4043: Loss of imprinting of KCNK9 in breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL KCNK9 (TASK-3) encodes a two-pore potassium channel that functions in tumor growth and survival. The potassium channel function is necessary for tumor proliferation and survival, by enhancing resistance to hypoxia and apoptosis. KCNK9 overexpression is observed in melanoma, colorectal cancer, and breast and brain tumors, but with no associated mutations found. Rather, the overexpression is often the apparent result of gene amplification of KCNK9, but any other mechanism that increases expression would presumably have a similar effect on tumorigenesis. This importance of gene dosage and expression levels is particularly relevant, as KCNK9 has been demonstrated to be a maternally expressed imprinted gene, which, in effect, reduces copy number. Monoallelic expression of KCNK9 was originally found in brain tissue, but our work has found that it is also imprinted in breast tissue. Thus, we hypothesized that loss of imprint control would be similar to a gene duplication, increasing the effective copy number, and therefore KCNK9 gene expression. To study the regulation of KCNK9 imprinting in tumors, we have screened for differentially methylated regions that may function as imprint control regions (ICRs), and examined the expression status of KCNK9 in breast tumor samples relative to the methylation state of the putative ICRs. Approximately 40-50% of breast tumor samples analyzed show loss of imprinting, seen as expression of both alleles of an exonic polymorphism. Additionally, loss of methylation at a putative ICR upstream of the transcription start site is observed in combination with loss of imprint regulation. This correlated loss of methylation and imprint control is seen most commonly in tumors of the “triple negative” subtype - tumors negative for expression of estrogen receptor, progesterone receptor, and HER2/neu. These novel findings regarding KCNK9 imprint regulation and its disruption in a subset of tumors may lead to new approaches in diagnosis and targeted therapy of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4043. doi:1538-7445.AM2012-4043