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

Abstract

BackgroundUnderstanding 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.MethodsIn 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.ResultsWe 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.ConclusionsWe 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.

miR-9-Mediated Inhibition of EFEMP1 Contributes to the Acquisition of Pro-Tumoral Properties in Normal Fibroblasts

“…Interestingly, mCAFs are highly associated with a stroma-derived invasion signature predictive of responsiveness to neoadjuvant chemotherapy in breast cancer [18]. Numerous clinical trials are currently revaluating cisplatin as chemotherapeutic option to treat TNBC, especially those harbouring a BRCA mutation [24,33]. As expected, our data show that lower BRCA1 expression is found in cisplatin responder patients, compared to non-responders.…”

Cancer cell-selective modulation of mitochondrial respiration and metabolism by potent organogold(iii) dithiocarbamates

“…The cytotoxicity of complexes 1a and 2a towards TNBC's is quite promising as these cell lines are typically cisplatin resistant. 75,76 Drug resistance is an ever-increasing problem in medicine so developing therapeutics for refractory tumours is of great importance. 77 To test the selectivity of compounds 1a and 2a for cancer cells over normal cells, we evaluated these complexes in the normal retinal epithelial cells using the MTT assay.…”

Do Olive and Fish Oils of the Mediterranean Diet Have a Role in Triple Negative Breast Cancer Prevention and Therapy? An Exploration of Evidence in Cells and Animal Models

“…Cisplatin is a platinum-based chemotherapy that demonstrated efficacy as a first-line chemotherapy in TNBC patients ( 117 ). However, multiple mechanisms of cisplatin-resistance have been identified in TNBC cells ( 118 ). Despite the potential deleterious effects of oleic acid on TNBC cells, one study demonstrated a potential synergistic relationship between oleate and Cisplatin on inducing apoptosis in MDA-MB-231 cells ( 68 ).…”