Oncotarget

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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

Sílvia Cufí, Bruna Corominas-Faja, Alejandro Vazquez-Martin, Cristina Oliveras-Ferraros, Joan Dorca, Joaquim Bosch-Barrera, Begoña Martin-Castillo and Javier A Menendez _

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Oncotarget. 2012; 3:395-398. https://doi.org/10.18632/oncotarget.488

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Abstract

Sílvia Cufí1,2, Bruna Corominas-Faja1,2, Alejandro Vazquez-Martin1,2, Cristina Oliveras-Ferraros1,2, Joan Dorca2,3, Joaquim Bosch-Barrera2,3, Begoña Martin-Castillo2,4, Javier A. Menendez1,2

1 Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Spain

2 Girona Biomedical Research Institute (IDIBGi), Girona, Spain

3 Medical Oncology, Catalan Institute of Oncology (ICO), Girona, Spain

4 Clinical Research Unit, Catalan Institute of Oncology (ICO), Girona, Spain

Received: April 27, 2012, Accepted: April 28, 2012, Published: May 4, 2012,

Keywords: Metformin, trastuzumab, HER2, cancer stem cells, breast cancer

Correspondence:

Javier A. Menendez, email:

Abstract

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.


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