The Role Of Genetic Variation In Calcium-Activated Potassium Channels In Breast Cancer Patients Treated With Tamoxifen

Potassium channels control membrane voltage and are essential for cell proliferation. Abnormal regulation and/or expression of these channels have been reported in cancer and result in dysregulated cell cycle progression, cell proliferation and migration. In breast cancer, clinical correlations of potassium channels have been associated with brain metastases, high stage, high grade, high proliferation, nodal status and poor prognosis. Interestingly, they have been associated with increased estrogen receptor (ER) expression. The selective ER modulator, tamoxifen, blocks estrogen from binding to the ER and is commonly used to treat patients with ER-positive breast cancer. However, up to 33% of patients treated with tamoxifen relapse or dies at 15 years of follow up. Both estrogen and tamoxifen have been demonstrated to activate potassium channels which then cause an increase in cell proliferation. In preliminary animal in vivo studies, we observed a better breast cancer prognosis in those with a knockout in potassium channel genes. Therefore, any alterations in the potassium channels may help to explain why patients treated with tamoxifen fail therapy. We hypothesized that genetic variation in potassium channels may affect breast cancer risk as well as tamoxifen treatment outcome. Genotyping was conducted on 45,290 breast cancer patients and 41,880 controls of European ancestry from 41 studies with the custom Illumina Infinium array (iCOGS). More than 200,000 SNPs were genotyped with over 11 million SNPs estimated using genotype imputation with SHAPEIT and IMPUTEv2 and the 1000 Genomes Project March 2012 release as the reference panel (Michailidou et al. Nature Genetics 2015). Variants from 13 potassium channels including KCNMA1, KCNMB1-4, KCNN1-4, LRRC26, LRRC38, LRRC52 and LRRC55 were analyzed. Of these, 3 imputed SNPs from KCNN4 have shown decreased breast cancer risk with GWAS significance (rs12463319, rs12609846, rs1685191; OR 0.94, P 0.05). These findings encouraged us to now further investigate the outcomes of patients with ER-positive breast cancer treated with tamoxifen. Survival data for 49,751 patients with a median follow-up of 8 years has been completed and released in November 2015. Of these, 32,571 were ER-positive and 10,383 have been treated with tamoxifen. Current efforts are underway in order to determine the effects of genetic variations in potassium channels on the survival of patients treated with tamoxifen. Our work will provide a better understanding of the potential clinical relevance of potassium channels in tamoxifen treatment in breast cancer. Citation Format: Wing-Yee Lo, Corinna Mohr, Friederike Steudel, Marjanka Schmidt, Douglas Easton, Reiner Hoppe, Werner Schroth, Peter Ruth, Robert Lukowski, Hiltrud Brauch, in collaboration with the Breast Cancer Association Consortium. The role of genetic variation in calcium-activated potassium channels in breast cancer patients treated with tamoxifen. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2030.