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22.06.2019 | Preclinical study | Ausgabe 2/2019

Breast Cancer Research and Treatment 2/2019

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

Zeitschrift:
Breast Cancer Research and Treatment > Ausgabe 2/2019
Autoren:
Corena V. Grant, Chase M. Carver, Shayne D. Hastings, Karthik Ramachandran, Madesh Muniswamy, April L. Risinger, John A. Beutler, Susan L. Mooberry
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s10549-019-05324-7) contains supplementary material, which is available to authorized users.

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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.

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Zusatzmaterial
Supplementary material 1 (PPT 2752 kb)
10549_2019_5324_MOESM1_ESM.ppt
Literatur
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