“In Preclinical Models, Bk Channel Subunits Influence Responses to Endocrine Therapy and Encourage the Development of Breast Cancer.”

Abstract

Context and Objective: Breast tumour cells with malignant characteristics are encouraged by pore-forming α subunits of the voltage- and Ca2+-activated K+ channel with large conductance (BKα). Leucine-rich repeat containing 26 (LRRC26) protein, also known as BKγ1, is one example of an auxiliary component that may be needed to enable BK current activation at a depolarized resting membrane potential, which is commonly observed in non-excitable tumor cells.

 Experimental Methodology The anti-tumor effects of BKα loss were studied in primary MMTV-PyMT cell cultures, a syngeneic transplantation model of breast cancer produced from these cells, and breast tumor-bearing MMTV-PyMT transgenic BKα knockout (KO) mice. In the context of endocrine therapy, the therapeutic value of BK channels was evaluated using human breast cancer cell lines that expressed high (MDA-MB-453) or low (MCF-7) levels of BKα and BKγ1 and in MDA-MB-157 that is BKα-negative Important Findings In preclinical models, BKα enhanced the onset and overall survival of breast cancer. On the other hand, the in vitro proliferation of human and murine breast cancer cells was inhibited by BKγ knockdown or absence of BKα. Tamoxifen and its main active metabolites, at low doses, increased BKα/γ1-positive breast cancer cell proliferation without affecting the estrogen receptor-controlled genomic signaling. Lastly, tamoxifen lengthened the BKα KO recipient mice's relative survival time, but not that of the wild-type tumor cell recipient mice

Conclusion and Significance Functional BK channels are necessary for the initiation, development, and tamoxifen sensitivity of breast cancer. This supports further research into the role of BK channels in carcinogenesis and how anti-estrogen medication affects clinical outcomes