SK4 channels modulate Ca 2+ signalling and cell cycle progression in murine breast cancer

• Published in: Molecular oncology 2017-09, Vol.11 (9), p.1172-1188
• Main Authors: Steudel, Friederike A, Mohr, Corinna J, Stegen, Benjamin, Nguyen, Hoang Y, Barnert, Andrea, Steinle, Marc, Beer-Hammer, Sandra, Koch, Pierre, Lo, Wing-Yee, Schroth, Werner, Hoppe, Reiner, Brauch, Hiltrud, Ruth, Peter, Huber, Stephan M, Lukowski, Robert
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Signaling; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Intermediate-Conductance Calcium-Activated Potassium Channels - metabolism; Intracellular Space - metabolism; Kaplan-Meier Estimate; Male; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Mammary Tumor Virus, Mouse - metabolism; Mice; Time Factors
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12087

Oncogenic signalling via Ca -activated K channels of intermediate conductance (SK4, also known as K 3.1 or IK) has been implicated in different cancer entities including breast cancer. Yet, the role of endogenous SK4 channels for tumorigenesis is unclear. Herein, we generated SK4-negative tumours by crossing SK4-deficient (SK4 KO) mice to the polyoma middle T-antigen (PyMT) and epidermal growth factor receptor 2 (cNeu) breast cancer models in which oncogene expression is driven by the retroviral promoter MMTV. Survival parameters and tumour progression were studied in cancer-prone SK4 KO in comparison with wild-type (WT) mice and in a syngeneic orthotopic mouse model following transplantation of SK4-negative or WT tumour cells. SK4 activity was modulated by genetic or pharmacological means using the SK4 inhibitor TRAM-34 in order to establish the role of breast tumour SK4 for cell growth, electrophysiological signalling, and [Ca ] oscillations. Ablation of SK4 and TRAM-34 treatment reduced the SK4-generated current fraction, growth factor-dependent Ca entry, cell cycle progression and the proliferation rate of MMTV-PyMT tumour cells. In vivo, PyMT oncogene-driven tumorigenesis was only marginally affected by the global lack of SK4, whereas tumour progression was significantly delayed after orthotopic implantation of MMTV-PyMT SK4 KO breast tumour cells. However, overall survival and progression-free survival time in the MMTV-cNeu mouse model were significantly extended in the absence of SK4. Collectively, our data from murine breast cancer models indicate that SK4 activity is crucial for cell cycle control. Thus, the modulation of this channel should be further investigated towards a potential improvement of existing antitumour strategies in human breast cancer.