Cisplatin-resistant triple-negative breast cancer subtypes: multiple mechanisms of resistance.
Animals
Antineoplastic Agents
/ therapeutic use
Biological Evolution
Cell Line, Tumor
Cisplatin
/ therapeutic use
Conserved Sequence
Drug Resistance, Neoplasm
/ genetics
Epithelial-Mesenchymal Transition
/ genetics
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genomics
/ methods
Humans
Mice
Rats
Receptors, Androgen
/ metabolism
Triple Negative Breast Neoplasms
/ drug therapy
Cancer genomics
Cancer subtypes
Cisplatin
Cisplatin sensitivity
Data mining
Drug response
Functional genomics
Gene expression
TNBC
Triple-negative breast cancer
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
04 Nov 2019
04 Nov 2019
Historique:
received:
24
01
2019
accepted:
21
10
2019
entrez:
6
11
2019
pubmed:
7
11
2019
medline:
4
4
2020
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
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.
Identifiants
pubmed: 31684899
doi: 10.1186/s12885-019-6278-9
pii: 10.1186/s12885-019-6278-9
pmc: PMC6829976
doi:
Substances chimiques
Antineoplastic Agents
0
Receptors, Androgen
0
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1039Subventions
Organisme : NHGRI NIH HHS
ID : R25 HG007053
Pays : United States
Organisme : NIH HHS
ID : AA018776
Pays : United States
Organisme : NCI NIH HHS
ID : P30CA034196
Pays : United States
Organisme : NHGRI NIH HHS
ID : U41 HG000330
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA018776
Pays : United States
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