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

• Published in: Breast cancer research and treatment Vol. 126; no. 2; pp. 355 - 364
• Main Authors: Vazquez-Martin, Alejandro, Oliveras-Ferraros, Cristina, Barco, Sonia Del, Martin-Castillo, Begoña, Menendez, Javier A
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.04.2011; Springer US; Springer; Springer Nature B.V; Springer Verlag
• Subjects: Analysis; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal, Humanized; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biological products; Biomarkers, Tumor - metabolism; Breast cancer; Breast carcinoma; Breast Neoplasms - pathology; Cancer; Cancer research; Cancer therapies; CD24 Antigen - metabolism; Cell culture; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Diabetes; Diabetes therapy; Drug Resistance, Neoplasm; Drug Synergism; Drugs; ErbB-2 protein; Female; Flow cytometry; Genetic aspects; Gynecology. Andrology. Obstetrics; HER2; Humans; Hyaluronan Receptors - metabolism; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Metformin; Metformin - pharmacology; Models, Biological; Monoclonal antibodies; Neoplastic Stem Cells - drug effects; Oncology; Phenotype; Preclinical Study; Receptor, ErbB-2 - metabolism; Stem cells; Toy industry; Trastuzumab; Tumor-initiating cells; Tumors; Tumor-initiating cells; Metformin; HER2; Trastuzumab; Stem cells; Antineoplastic agent; Cell proliferation; Breast disease; Stem cell; Breast tumor; erbB2 Gene; Monoclonal antibody; Hypoglycemic agent; Self renewal; Biguanides; Tumor cell; Protooncogene; Drug; Breast cancer; Malignant tumor; Human Epidermal growth factor Receptor 2; Resistance; Mammary gland diseases; C-Onc gene; Cancer
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-010-0924-x

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 CD44pos/CD24neg/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.