Document Type
Article
Publication Date
2020
College/Unit
School of Medicine
Department/Program/Center
Physiology, Pharmacology & Neuroscience
Abstract
Background
Unlike other breast cancer subtypes that may be treated with a variety of hormonal or targeted therapies, there is a need to identify new, effective targets for triple-negative breast cancer (TNBC). It has recently been recognized that membrane potential is depolarized in breast cancer cells. The primary objective of the study is to explore whether hyperpolarization induced by opening potassium channels may provide a new strategy for treatment of TNBC.
Methods
Breast cancer datasets in cBioPortal for cancer genomics was used to search for ion channel gene expression. Immunoblots and immunohistochemistry were used for protein expression in culture cells and in the patient tissues. Electrophysiological patch clamp techniques were used to study properties of BK channels in culture cells. Flow cytometry and fluorescence microscope were used for cell viability and cell cycle studies. Ultrasound imaging was used to study xenograft in female NSG mice.
Results
In large datasets of breast cancer patients, we identified a gene, KCNMA1 (encoding for a voltage- and calcium-dependent large-conductance potassium channel, called BK channel), overexpressed in triple-negative breast cancer patients. Although overexpressed, 99% of channels are closed in TNBC cells. Opening BK channels hyperpolarized membrane potential, which induced cell cycle arrest in G2 phase and apoptosis via caspase-3 activation. In a TNBC cell induced xenograft model, treatment with a BK channel opener significantly slowed tumor growth without cardiac toxicity.
Conclusions
Our results support the idea that hyperpolarization induced by opening BK channel in TNBC cells can become a new strategy for development of a targeted therapy in TNBC.
Digital Commons Citation
Sizemore, Gina; McLaughlin, Sarah; Newman, Mackenzie; Brundage, Kathleen; Ammer, Amanda; Martin, Karen; Pugacheva, Elena; Coad, James; Mattes, Malcolm D.; and Yu, Han-Gang, "Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer" (2020). Faculty & Staff Scholarship. 3027.
https://researchrepository.wvu.edu/faculty_publications/3027
Source Citation
Sizemore, G., McLaughlin, S., Newman, M. et al. Opening large-conductance potassium channels selectively induced cell death of triple-negative breast cancer. BMC Cancer 20, 595 (2020). https://doi.org/10.1186/s12885-020-07071-1
Comments
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.