Subunits of BK channels promote breast cancer development and modulate responses to endocrine treatment in preclinical models
| Autor: | Dominic Gross, Stephan M. Huber, Stephen F. Madden, Benjamin Stegen, Robert Lukowski, Hiltrud Brauch, Severine Stehling, Alice Dragoi, Werner Schroth, Thomas E. Mürdter, Selina Maier, Corinna J. Mohr, Reiner Hoppe, Friederike A. Steudel, Peter Ruth |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
BK channel Cell Estrogen receptor Breast Neoplasms Mice Transgenic Context (language use) Membrane Potentials Mice 03 medical and health sciences 0302 clinical medicine Breast cancer Animals Humans Medicine Large-Conductance Calcium-Activated Potassium Channels skin and connective tissue diseases Mice Knockout Pharmacology biology business.industry medicine.disease Tamoxifen 030104 developmental biology medicine.anatomical_structure Cell culture Cancer cell biology.protein Cancer research Female business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | British Journal of Pharmacology. 179:2906-2924 |
| ISSN: | 1476-5381 0007-1188 |
| Popis: | Background and purpose Pore-forming α subunits of the voltage- and Ca2+ -activated K+ channel with large conductance (BKα) promote malignant phenotypes of breast tumour cells. Auxiliary subunits such as the leucine-rich repeat containing 26 (LRRC26) protein, also termed BKγ1, may be required to permit activation of BK currents at a depolarized resting membrane potential that frequently occur in non-excitable tumour cells. Experimental approach Anti-tumour effects of BKα loss were investigated in breast tumour-bearing MMTV-PyMT transgenic BKα knockout (KO) mice, primary MMTV-PyMT cell cultures, and in a syngeneic transplantation model of breast cancer derived from these cells. The therapeutic relevance of BK channels in the context of endocrine treatment was assessed in human breast cancer cell lines expressing either low (MCF-7) or high (MDA-MB-453) levels of BKα and BKγ1, as well as in BKα-negative MDA-MB-157. Key results BKα promoted breast cancer onset and overall survival in preclinical models. Conversely, lack of BKα and/or knockdown of BKγ1 attenuated proliferation of murine and human breast cancer cells in vitro. At low concentrations, tamoxifen and its major active metabolites stimulated proliferation of BKα/γ1-positive breast cancer cells, independent of the genomic signalling controlled by the oestrogen receptor. Finally, tamoxifen increased the relative survival time of BKα KO but not of wild-type tumour cell recipient mice. Conclusion and implications Breast cancer initiation, progression, and tamoxifen sensitivity depend on functional BK channels thereby providing a rationale for the future exploration of the oncogenic actions of BK channels in clinical outcomes with anti-oestrogen therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text