Breast Cancer Research and Treatment

, Volume 113, Issue 1, pp 101–111 | Cite as

Therapeutic metformin/AMPK activation promotes the angiogenic phenotype in the ERα negative MDA-MB-435 breast cancer model

  • Kathryn N. Phoenix
  • Frank Vumbaca
  • Kevin P. Claffey
Preclinical Study

Abstract

Metformin, a first line treatment for type 2 diabetes, has been implicated as a potential anti-neoplastic agent for breast cancers as well as other cancers. Metformin is known to work in part through the activation of AMP-dependent kinase (AMPK). AMPK is a key regulator of cellular energy homeostasis, especially under stress conditions where biosynthetic pathways are blocked by the phosphorylation of downstream AMPK substrates. Stimulation of AMPK by metformin resulted in a significant repression of cell proliferation and active MAPK1/2 in both estrogen receptor α (ERα) negative (MDA-MB-231, MDA-MB-435) and positive (MCF-7, T47D) human breast cancer cell lines. However, when ERα negative MDA-MB-435 cells were treated with metformin, they demonstrated increased expression of vascular endothelial growth factor (VEGF) in an AMPK dependent manner; while the ERα positive MCF-7 cells did not. Systemic therapy with metformin was tested for efficacy in an orthotopic model of ERα negative breast cancer performed in athymic nude mice. Surprisingly, metformin therapy significantly improved tumorigenic progression as compared to untreated controls. The metformin-treated group showed increased VEGF expression, intratumoral microvascular density and reduced necrosis. Metformin treatment was sufficient, however, to reduce systemic IGF-1 and the proliferation rate of tumor cells in vascularized regions. The data presented here suggests that, although metformin significantly represses breast cancer cell growth in vitro, the efficacy with respect to its therapeutic application for ERα negative breast cancer lesions in vivo may result in promotion of the angiogenic phenotype and increased tumorigenic progression.

Keywords

AMPK Angiogenesis Breast carcinoma MAPK Metformin VEGF 

Supplementary material

10549_2008_9916_MOESM1_ESM.tif (11.6 mb)
ESM1 (TIF 11899 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Kathryn N. Phoenix
    • 1
  • Frank Vumbaca
    • 1
  • Kevin P. Claffey
    • 1
  1. 1.Center for Vascular Biology, EM028, Department of Cell Biology-MC3501University of Connecticut Health CenterFarmingtonUSA

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