K _Ca3.1 Channels Confer Radioresistance to Breast Cancer Cells

Abstract

K _Ca3.1 K ⁺ channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K _Ca3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K _Ca3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K _Ca3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K _Ca3.1 for therapy response. The K _Ca3.1 status of MMTV-PyMT cells did not determine tumor cell proliferation after treatment with different concentrations of docetaxel, doxorubicin, 5-fluorouracil, or cyclophosphamide. K _Ca3.1 activation by ionizing radiation (IR) in breast tumor cells in vitro, however, enhanced radioresistance, probably via an involvement of the channel in IR-stimulated Ca ²⁺ signals and DNA repair pathways. Consistently, K _Ca3.1 knockout increased survival time of wildtype mice upon syngeneic orthotopic transplantation of MMTV-PyMT tumors followed by fractionated radiotherapy. Combined, our results imply that K _Ca3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K _Ca3.1 is druggable, K _Ca3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors.