Role of Ca2+-activated K+ Channels in Breast Cancer Proliferation and Resistance to Cytotoxic Drugs and Radiation

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Our analyses in genetic mouse tumor models suggest an important role of Ca2+-activated K+ channels (KCa) of big (BK) and intermediate (SK4 or IK) conductance in tumor cell proliferation and migration. Previously, we have interbred three genetic mouse models for mammary carcinoma (MMTV/c-neu), glioblastoma (NF1/TRP53) and prostate carcinoma (TRAMP) with BK-/- and SK4-/- mice, respectively. Kaplan-Meier-analyses supported by MRI/PET, showed in BK-/- mice a complete prevention and in SK4-/- mice a partial suppression of mammary tumor onset and progression. In the glioblastoma model the survival of BK-/- animals was prolonged by 90 days, while prostate cancer-bearing mice did not significantly benefit from BK or SK4 ablation. Hence, we will investigate the potential of SK4 and BK channel blockers to prevent tumor growth and overcome therapy resistance of MMTV/c-neu tumors. The analysis of additional breast cancer models (e.g. MMTV/PyMT) will show whether the protective effects of BK and SK4 ablation in MMTV/c-neu mice are of general importance for mammary tumor onset and progression. Aiming toward the identification of the cellular and molecular mechanisms, we will use native tumor tissues and primary tumor cells to characterize e.g. Ca2+ signaling, cell cycle processes and cytotoxic drug and irradiation responses in the absence and presence of KCa blockers. To validate that the in vivo effects are caused by KCa deficiency of tumor cells and not indirectly mediated differences in vascularization or immune responses of the recipient mice, allotransplantation studies will be performed by transferring primary tumor cells to BK-/- and SK4-/- mice. In this line, tumor-specific BK mutants generated in MMTV-Cre-mice will also allow us to separate primary from secondary anti-tumor effects of BK inactivation. Furthermore, immunocompromised mice will be used as tumor transplant recipients to propagate KCa-deficient and wild-type primary tumors and cells derived thereof. By comparing the growth of the engraftments and their resistance to different chemo- and radiotherapy regimes, the importance of KCa for a pharmacological intervention can be evaluated.