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Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype.

ABSTRACT: PURPOSE:Triple-negative breast cancers (TNBCs) represent a heterogeneous group of tumors. The lack of targeted therapies combined with the inherently aggressive nature of TNBCs results in a higher relapse rate and poorer overall survival. We evaluated the heterogeneity of TNBC cell lines for TRPC channel expression and sensitivity to cation-disrupting drugs. METHODS:The TRPC1/4/5 agonist englerin A was used to identify a group of TNBC cell lines sensitive to TRPC1/4/5 activation and intracellular cation disruption. Quantitative RT-PCR, the sulforhodamine B assay, pharmacological inhibition, and siRNA-mediated knockdown approaches were employed. Epifluorescence imaging was performed to measure intracellular Ca2+ and Na+ levels. Mitochondrial membrane potential changes were monitored by confocal imaging. RESULTS:BT-549 and Hs578T cells express high levels of TRPC4 and TRPC1/4, respectively, and are exquisitely, 2000- and 430-fold, more sensitive to englerin A than other TNBC cell lines. While englerin A caused a slow Na+ and nominal Ca2+ accumulation in Hs578T cells, it elicited rapid increases in cytosolic Ca2+ levels that triggered mitochondrial depolarization in BT-549 cells. Interestingly, BT-549 and Hs578T cells were also more sensitive to digoxin as compared to other TNBC cell lines. Collectively, these data reveal TRPC1/4 channels as potential biomarkers of TNBC cell lines with dysfunctional mechanisms of cation homeostasis and therefore sensitivity to cardiac glycosides. CONCLUSIONS:The sensitivity of BT-549 and Hs578T cells to englerin A and digoxin suggests a subset of TNBCs are highly susceptible to cation disruption and encourages investigation of TRPC1 and TRPC4 as potential new biomarkers of sensitivity to cardiac glycosides.

SUBMITTER: Grant CV

PROVIDER: S-EPMC6730645 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype.

Grant Corena V CV Carver Chase M CM Hastings Shayne D SD Ramachandran Karthik K Muniswamy Madesh M Risinger April L AL Beutler John A JA Mooberry Susan L SL

Breast cancer research and treatment 20190622 2

<h4>Purpose</h4>Triple-negative breast cancers (TNBCs) represent a heterogeneous group of tumors. The lack of targeted therapies combined with the inherently aggressive nature of TNBCs results in a higher relapse rate and poorer overall survival. We evaluated the heterogeneity of TNBC cell lines for TRPC channel expression and sensitivity to cation-disrupting drugs.<h4>Methods</h4>The TRPC1/4/5 agonist englerin A was used to identify a group of TNBC cell lines sensitive to TRPC1/4/5 activation a ...[more]

PMID: 31230251

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Project description:Triple-negative breast cancer (TNBC) is a highly heterogeneous group of cancers, and molecular subtyping is necessary to better identify molecular-based therapies. While some classifiers have been established, no one has integrated the expression profiles of long noncoding RNAs (lncRNAs) into such subtyping criterions. Considering the emerging important role of lncRNAs in cellular processes, a novel classification integrating transcriptome profiles of both messenger RNA (mRNA) and lncRNA would help us better understand the heterogeneity of TNBC.Using human transcriptome microarrays, we analyzed the transcriptome profiles of 165 TNBC samples. We used k-means clustering and empirical cumulative distribution function to determine optimal number of TNBC subtypes. Gene Ontology (GO) and pathway analyses were applied to determine the main function of the subtype-specific genes and pathways. We conducted co-expression network analyses to identify interactions between mRNAs and lncRNAs.All of the 165 TNBC tumors were classified into four distinct clusters, including an immunomodulatory subtype (IM), a luminal androgen receptor subtype (LAR), a mesenchymal-like subtype (MES) and a basal-like and immune suppressed (BLIS) subtype. The IM subtype had high expressions of immune cell signaling and cytokine signaling genes. The LAR subtype was characterized by androgen receptor signaling. The MES subtype was enriched with growth factor signaling pathways. The BLIS subtype was characterized by down-regulation of immune response genes, activation of cell cycle, and DNA repair. Patients in this subtype experienced worse recurrence-free survival than others (log rank test, P = 0.045). Subtype-specific lncRNAs were identified, and their possible biological functions were predicted using co-expression network analyses.We developed a novel TNBC classification system integrating the expression profiles of both mRNAs and lncRNAs and determined subtype-specific lncRNAs that are potential biomarkers and targets. If further validated in a larger population, our novel classification system could facilitate patient counseling and individualize treatment of TNBC.

Dataset Information

Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype.

Publications

Triple-negative breast cancer cell line sensitivity to englerin A identifies a new, targetable subtype.

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