KCa channels in breast cancer development, progression and response to endocrine and radiation therapy

Abstract

Breast cancer is the most frequent malignancy and second leading cause of cancer death of women in the Western world [1]. New targets and therapeutic strategies are necessary to improve existing therapies and to overcome therapy failure and resistance. Altered expression or activity of Ca2+-activated K+ channels of big (BK) and intermediate (IK) conductance promotes growth, migration and survival of breast tumour cells [2]. Spontaneous breast cancer-prone MMTV-PyMTtg/+ BK or IK knockout (KO) and control mice, primary tumour cells derived thereof and an orthotopic allotransplant model were used to study tumour development, proliferation and growth as well as the response to endocrine therapy and radiotherapy. The translational relevance was investigated in human MCF-7, MDA-MB-157 and MDA-MB-453 breast tumour cells and in open access public databases such as The Cancer Genome Atlas. Finally, variants in KCa channel genes as cause for breast cancer were assessed with data used from the Breast Cancer Association Consortium. BK was a good prognostic marker for tumour onset and progression in the MMTV-PyMTtg/+ model, whereas the interaction between tumour cells and immune cells infiltrating into the tumour determined the oncogenic action of IK in vivo. Single nucleotide polymorphisms in the BK accessory beta4 subunit and IK channel genes were found to modulate human risk to develop oestrogen receptor (ER)-positive breast cancer [3]. In addition, BK and IK mRNA expression levels showed significant impact on overall survival outcome in breast cancer patients. BK, probably by interacting with its accessory beta1 subunit, and IK promoted cell proliferation in vitro. For BK, this effect was promoted by serum-derived growth factors and hormones such as 17beta-oestradiol. Surprisingly, however, also anti-oestrogens such as tamoxifen and its metabolites promoted rather than inhibited cell proliferation in vitro and tumour progression in vivo in dependence on BK. With regard to radiotherapy, IK contributed to DNA repair and clonogenic survival in vitro as well as tumour progression after irradiation in vivo. Collectively, these data demonstrate the impact of BK and IK channels in breast cancer development, progression and survival outcome. Oncogenic signalling via BK and IK seems to affect the success of endocrine or radiation therapy in the management of breast cancer. 1 Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J Clin 66, 7-30, doi:10.3322/caac.21332 (2016). 2 Pardo, L. A. & Stuhmer, W. The roles of K(+) channels in cancer. Nat Rev Cancer 14, 39-48, doi:10.1038/nrc3635 (2014). 3 Michailidou, K. et al. Association analysis identifies 65 new breast cancer risk loci. Nature 551, 92-94, doi:10.1038/nature24284 (2017).