Abstract
BackgroundDeveloping novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC.MethodsRepresentative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44+ and CD24-/low, or Aldefluor+) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro.ResultsAlthough there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone.ConclusionsOverall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0662-4) contains supplementary material, which is available to authorized users.
Highlights
Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge
We investigated whether the breast cancer stem cells (CSC) population enriched for tumorigenic CD44+CD24−/low cells could be eradicated when treated with Cetuximab and Ixabepilone, as opposed to chemotherapy alone, in TNBC xenografts
Cell proliferation and viability measurements (WST-1 assay) TNBC cell lines MDA-MB-231 and SUM159 were purchased from American Type Culture Collection (ATCC), Manassas, VA, USA, and from Asterand, Detroit, MI, USA, These cell lines were chosen based on their high expression of epithelial-mesenchymal transition markers (EMT), metastatic properties, and percentage of CD44+ /CD24cells
Summary
Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance These characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Triple-negative breast cancer (TNBC), which accounts for 20 % of all breast cancers, is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression They are histologically high grade, aggressive, and lethal tumor types that lack targeted therapeutic options. Tanei et al Breast Cancer Research (2016) 18:6 colleagues isolated a cell population characterized by high CD44 expression and low or undetectable levels of CD24 (CD44+/CD24−/low) These cells had classic features of bona fide stem cells, including the capacity for selfrenewal and generation of heterogeneous progeny [8]. TNBC can be classified as basal type cancer defined by EGFR and cytokeratin 5/6 staining
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