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The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells.

Catalan Institute of Oncology, Girona (ICO-Girona), Dr. Josep Trueta University Hospital, Ctra. França s/n, 17007, Girona, Catalonia, Spain.
Breast Cancer Research and Treatment (Impact Factor: 4.2). 05/2010; 126(2):355-64. DOI: 10.1007/s10549-010-0924-x
Source: PubMed

ABSTRACT We here demonstrate that the anti-diabetic drug metformin interacts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin™) to eliminate stem/progenitor cell populations in HER2-gene-amplified breast carcinoma cells. When using the mammosphere culture technique, graded concentrations of single-agent metformin (range 50-1,000 μmol/l) were found to dose-dependently reduce the number of mammospheres formed by SKBR3 (a Tzb-naïve model), SKBR3 TzbR (a model of acquired auto-resistance to Tzb) and JIMT-1 (a model of refractoriness to Tzb and other HER2-targeted therapies ab initio) HER2-overexpressing breast cancer cells. Single-agent Tzb likewise reduced mammosphere-forming efficiency (MSFE) in Tzb-naïve SKBR3 cells, but it failed to significantly decrease MSFE in Tzb-resistant SKBR3 TzbR and JIMT-1 cells. Of note, CD44-overexpressing Tzb-refractory SKBR3 TzbR and JIMT-1 cells retained an exquisite sensitivity to single-agent metformin. Concurrent combination of metformin with Tzb synergistically reduced MSFE as well as the size of mammospheres in Tzb-refractory SKBR3 TzbR and JIMT-1 cells. Flow cytometry analyses confirmed that metformin and Tzb functioned synergistically to down-regulate the percentage of Tzb-refractory JIMT-1 cells displaying the CD44(pos)/CD24(neg/low) stem/progenitor immunophenotype. Given that MSFE and mammosphere size are indicators of stem self-renewal and progenitor cell proliferation, respectively, our current findings reveal for the first time that: (a) Tzb refractoriness in HER2 overexpressors can be explained in terms of Tzb-resistant/CD44-overexpressing/tumor-initiating stem cells; (b) metformin synergistically interacts with Tzb to suppress self-renewal and proliferation of cancer stem/progenitor cells in HER2-positive carcinomas.

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