Corinna J Mohr1,2, Werner Schroth2, Thomas E Mürdter2, Dominic Gross1, Selina Maier1,2, Benjamin Stegen3, Alice Dragoi1, Friederike A Steudel1, Severine Stehling1, Reiner Hoppe2, Stephen Madden4, Peter Ruth1, Stephan M Huber3, Hiltrud Brauch2,5,6, Robert Lukowski1. 1. Department of Pharmacology, Toxicology and Clinical Pharmacy, Institute of Pharmacy, University of Tuebingen, Tuebingen, Germany. 2. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Germany. 3. Department of Radiation Oncology, University of Tuebingen, Tuebingen, Germany. 4. RCSI Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland. 5. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. iFIT-Cluster of Excellence, University of Tuebingen, Tuebingen, Germany.
Abstract
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. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
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. LINKED ARTICLES: This article is part of a themed issue on New avenues in cancer prevention and treatment (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.12/issuetoc.
Authors: Helmut Bischof; Sandra Burgstaller; Anna Springer; Lucas Matt; Thomas Rauter; Olaf A Bachkönig; Tony Schmidt; Klaus Groschner; Rainer Schindl; Tobias Madl; Nikolaus Plesnila; Robert Lukowski; Wolfgang F Graier; Roland Malli Journal: iScience Date: 2021-03-22
Authors: Sandra Burgstaller; Teresa R Wagner; Helmut Bischof; Sarah Bueckle; Aman Padamsey; Desiree Frecot; Philipp D Kaiser; David Skrabak; Roland Malli; Robert Lukowski; Ulrich Rothbauer Journal: iScience Date: 2022-08-10