| Summary: | K<sub>Ca</sub>3.1 K<sup>+</sup> channels reportedly contribute to the proliferation of breast tumor cells and may serve pro-tumor functions in the microenvironment. The putative interaction of K<sub>Ca</sub>3.1 with major anti-cancer treatment strategies, which are based on cytotoxic drugs or radiotherapy, remains largely unexplored. We employed K<sub>Ca</sub>3.1-proficient and -deficient breast cancer cells derived from breast cancer-prone MMTV-PyMT mice, pharmacological K<sub>Ca</sub>3.1 inhibition, and a syngeneic orthotopic mouse model to study the relevance of functional K<sub>Ca</sub>3.1 for therapy response. The K<sub>Ca</sub>3.1 status of MMTV-PyMT cells did not determine tumor cell proliferation after treatment with different concentrations of docetaxel, doxorubicin, 5-fluorouracil, or cyclophosphamide. K<sub>Ca</sub>3.1 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<sup>2+</sup> signals and DNA repair pathways. Consistently, K<sub>Ca</sub>3.1 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<sub>Ca</sub>3.1 confers resistance to radio- but not to chemotherapy in the MMTV-PyMT breast cancer model. Since K<sub>Ca</sub>3.1 is druggable, K<sub>Ca</sub>3.1 targeting concomitant to radiotherapy seems to be a promising strategy to radiosensitize breast tumors.
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