Metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low cells is sufficient to overcome primary resistance to trastuzumab in HER2+ human breast cancer xenografts

Oncotarget. 2012 Apr;3(4):395-8. doi: 10.18632/oncotarget.488.


Trastuzumab-refractory breast cancer stem cells (CSCs) could also explain the high rate of primary resistance to single-agent trastuzumab in HER2 gene-amplified breast cancer patients. The identification of agents with strong selective toxicity for trastuzumab-resistant breast CSCs may have tremendous relevance for how HER2+ breast cancer patients should be treated. Using the human breast cancer cell line JIMT-1, which was established from the pleural metastasis of a patient who was clinically resistant to trastuzumab ab initio, we examined whether preferential killing of the putative CD44+CD24-/low breast CSC population might be sufficient to overcome primary resistance to trastuzumab in vivo. Because recent studies have shown that the anti-diabetic biguanide metformin can exert antitumor effects by targeted killing of CSC-like cells, we explored whether metformin's ability to preferentially kill breast cancer initiating CD44+CD24-/low cells may have the potential to sensitize JIMT-1 xenograft mouse models to trastuzumab. Upon isolation for breast cancer initiating CD44+CD24-/low cells by employing magnetic activated cell sorting, we observed the kinetics of metformin-induced killing drastically varied among CSC and non-CSC subpopulations. Metformin's cell killing effect increased dramatically by more than 10-fold in CD44+CD24-/low breast CSC cells compared to non-CD44+CD24-/low immunophenotypes. While seven-weeks treatment length with trastuzumab likewise failed to reduce tumor growth of JIMT-1 xenografts, systemic treatment with metformin as single agent resulted in a significant two-fold reduction in tumor volume. When trastuzumab was combined with concurrent metformin, tumor volume decreased sharply by more than four-fold. Given that metformin-induced preferential killing of breast cancer initiating CD44+CD24-/low subpopulations is sufficient to overcome in vivo primary resistance to trastuzumab, the incorporation of metformin into trastuzumab-based regimens may provide a valuable strategy for treatment of HER2+ breast cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • CD24 Antigen / metabolism
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Hyaluronan Receptors / metabolism
  • Metformin / administration & dosage
  • Metformin / adverse effects
  • Metformin / therapeutic use*
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal, Humanized
  • CD24 Antigen
  • Hyaluronan Receptors
  • Metformin
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab