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BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance

Authors: David P. Hill, Akeena Harper, Joan Malcolm, Monica S. McAndrews, Susan M. Mockus, Sara E. Patterson, Timothy Reynolds, Erich J. Baker, Carol J. Bult, Elissa J. Chesler, Judith A. Blake

Published in: BMC Cancer | Issue 1/2019

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Abstract

Background

Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies.

Methods

In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC.

Results

We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition.

Conclusions

We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.
Appendix
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Metadata
Title
Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance
Authors
David P. Hill
Akeena Harper
Joan Malcolm
Monica S. McAndrews
Susan M. Mockus
Sara E. Patterson
Timothy Reynolds
Erich J. Baker
Carol J. Bult
Elissa J. Chesler
Judith A. Blake
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-6278-9

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