Abstract 271: Rapid regulation of ion channel KCNK5 by ERα in breast cancer cell lines MCF-7 and T47D promotes cell proliferation

Abstract

Abstract Many human breast tumors rely on the proliferative effect of estrogen to propagate. Estrogenic compounds, such as the endogenous ligand 17β-estradiol, signals in various manners, most prominently through the estrogen receptors (ERs). The ERs – alpha and beta, respectively – are transcription factors belonging to the superfamily of nuclear receptors. They act by genomical and non-genomical mechanisms in a ligand-dependent as well as -independent manner, exerting ligand-, promoter- and tissue-specific transcriptional programs. Due to the proliferative effect of ERα in breast it is an important factor in tumor progression. ERα is used clinically as a biomarker and is therapeutically targeted by treatment with antagonistic compounds, for instance tamoxifen. Although extensively studied, the mechanism by which ERα promotes proliferation remains to be fully established. Here we present the finding that ERα rapidly upregulates the potassium ion channel KCNK5 (TASK-2, K2P5.1) in human breast cancer cell lines MCF-7 and T47D. ERα binds at the enhancer of the KCNK5 gene upon estrogen stimulation, subsequently inducing increases in transcript and protein levels of KCNK5. The observed upregulation was strikingly quick, with a sharp peak within one to two hours, before leveling off. Protein levels, however, did not increase until after 12 hours. Treatment with compounds antagonizing ERα transactivation efficiently suppressed this upregulation, further supporting the notion of direct ERα regulation, as compared to non-genomic signaling. Estrogen treatment also increased KCNK5 currents in both cell lines. Various roles for potassium channels in cancer cells have previously been suggested, as for example proliferative, metastatic and anti-apoptotic factors. Knockdown of KCNK5 by siRNA in MCF-7 and T47D cells decreased their proliferation. Additionally, in T47D cells, the estrogen-induced proliferation was repressed when KCNK5 was silenced. This prompts further studies to understand the role of KCNK5 in the proliferation of breast cancer cells and clinical relevance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 271. doi:10.1158/1538-7445.AM2011-271