TY - JOUR
T1 - Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells
AU - Tanei, Tomonori
AU - Choi, Dong Soon
AU - Rodriguez, Angel A.
AU - Liang, Diana Hwang
AU - Dobrolecki, Lacey
AU - Ghosh, Madhumita
AU - Landis, Melissa D.
AU - Chang, Jenny C.
N1 - Funding Information:
We thank Dr. Gary Deyter for critical reading and editing of the manuscript. This research is supported by grants from the Breast Cancer Research Foundation; Komen Promise for the Cure KG081694; National Institutes of Health NIH U54 CA 149196; NIHR01 CA138197; Golfer’s Against Cancer; Team Tiara; Causes for a Cure.
Publisher Copyright:
© 2016 Tanei et al.
PY - 2016/1/12
Y1 - 2016/1/12
N2 - Background: 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. 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. Methods: Representative 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. Results: Although 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. Conclusions: Overall, 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.
AB - Background: 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. 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. Methods: Representative 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. Results: Although 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. Conclusions: Overall, 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.
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U2 - 10.1186/s13058-015-0662-4
DO - 10.1186/s13058-015-0662-4
M3 - Article
C2 - 26757880
AN - SCOPUS:84954403089
VL - 18
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
IS - 1
M1 - 6
ER -