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Research Article

Metformin Selectively Targets Tumor-Initiating Cells in ErbB2-Overexpressing Breast Cancer Models

Pei Zhu, Meghan Davis, Amanda J. Blackwelder, Nora Bachman, Bolin Liu, Susan Edgerton, Leonard L. Williams, Ann D. Thor and Xiaohe Yang
Pei Zhu
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Meghan Davis
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Amanda J. Blackwelder
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Nora Bachman
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Bolin Liu
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Susan Edgerton
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Leonard L. Williams
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Ann D. Thor
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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Xiaohe Yang
Authors' Affiliations: Julis L. Chambers Biomedical/Biotechnology Research Institute; North Carolina Central University; Kannapolis, North Carolina; Biotechnology; Rowan-Cabarrus Community College; Kannapolis, North Carolina; Department of Pathology; University of Colorado; Anschutz Medical Campus; Aurora, Colorado; Center for Excellence in Post Harvest Technologies; North Carolina A&T State University; Kannapolis, North Carolina
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DOI: 10.1158/1940-6207.CAPR-13-0181 Published February 2014
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Abstract

Metformin is an oral biguanide used for type II diabetes. Epidemiologic studies suggest a link between metformin use and reduced risk of breast and other types of cancers. ErbB2-expressing breast cancer is a subgroup of tumors with poor prognosis. Previous studies demonstrated that metformin is a potent inhibitor of ErbB2–overexpressing breast cancer cells; metformin treatment extends the life span and impedes mammary tumor development in ErbB2 transgenic mice in vivo. However, the mechanisms of metformin associated antitumor activity, especially in prevention models, remain unclear. We report here for the first time that systemic administration of metformin selectively inhibits CD61high/CD49fhigh subpopulation, a group of tumor-initiating cells (TIC) of mouse mammary tumor virus (MMTV)-ErbB2 mammary tumors, in preneoplastic mammary glands. Metformin also inhibited CD61high/CD49fhigh subpopulation in MMTV-ErbB2 tumor-derived cells, which was correlated with their compromised tumor initiation/development in a syngeneic tumor graft model. Molecular analysis indicated that metformin induced downregulation of ErbB2 and EGFR expression and inhibited the phosphorylation of ErbB family members, insulin-like growth factor-1R, AKT, mTOR, and STAT3 in vivo. In vitro data indicate that low doses of metformin inhibited the self-renewal/proliferation of cancer stem cells (CSC)/TICs in ErbB2–overexpressing breast cancer cells. We further demonstrated that the expression and activation of ErbB2 were preferentially increased in CSC/TIC-enriched tumorsphere cells, which promoted their self-renewal/proliferation and rendered them more sensitive to metformin. Our results, especially the in vivo data, provide fundamental support for developing metformin-mediated preventive strategies targeting ErbB2–associated carcinogenesis. Cancer Prev Res; 7(2); 199–210. ©2013 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Received May 13, 2013.
  • Revision received November 12, 2013.
  • Accepted November 25, 2013.
  • ©2013 American Association for Cancer Research.
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Cancer Prevention Research: 7 (2)
February 2014
Volume 7, Issue 2
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Metformin Selectively Targets Tumor-Initiating Cells in ErbB2-Overexpressing Breast Cancer Models
Pei Zhu, Meghan Davis, Amanda J. Blackwelder, Nora Bachman, Bolin Liu, Susan Edgerton, Leonard L. Williams, Ann D. Thor and Xiaohe Yang
Cancer Prev Res February 1 2014 (7) (2) 199-210; DOI: 10.1158/1940-6207.CAPR-13-0181

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Metformin Selectively Targets Tumor-Initiating Cells in ErbB2-Overexpressing Breast Cancer Models
Pei Zhu, Meghan Davis, Amanda J. Blackwelder, Nora Bachman, Bolin Liu, Susan Edgerton, Leonard L. Williams, Ann D. Thor and Xiaohe Yang
Cancer Prev Res February 1 2014 (7) (2) 199-210; DOI: 10.1158/1940-6207.CAPR-13-0181
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