A major obstacle in the successful treatment of
cancer is the occurrence of chemoresistance.
Cancer cells surviving
chemotherapy and giving rise to a recurrence of the
tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in
cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2(high) and HER2(low) cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2(low) cell fraction. Accordingly, HER2(low) cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in
matrigel. Xenografts from subcutaneously injected HER2(low) sorted cells exihibited earlier onset but slower growth of
tumors and an increase in stem cell markers compared to
tumors developed from the HER2(high) fraction. Treatment of mammospheres with
salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells.
Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with
trastuzumab and
salinomycin was superior to single treatment with each
drug. Thus, targeting HER2 expressing
tumors with anti-HER2
therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive
cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy.