Abstract
Reports suggest that metformin, a popular anti-diabetes drug, prevents breast cancer through various systemic effects, including insulin-like growth factor receptor (IGFR) regulation. Although the anti-cancer properties of metformin have been well-studied, reports on a more bioavailable/potent biguanide, phenformin, remain sparse. Phenformin exerts similar functional activity to metformin and has been reported to impede mammary carcinogenesis in rats. Since the effects of phenformin on specific breast cancer subtypes have not been fully explored, we used ErbB2-overexpressing breast cancer cell and animal models to test the anti-cancer potential of phenformin. We report that phenformin (25–75 μM) decreased cell proliferation and impaired cell cycle progression in SKBR3 and 78617 breast cancer cells. Reduced tumor size after phenformin treatment (30 mg/kg/day) was demonstrated in an MMTV-ErbB2 transgenic mouse syngeneic tumor model. Phenformin also blocked epithelial-mesenchymal transition, decreased the invasive phenotype, and suppressed receptor tyrosine kinase signaling, including insulin receptor substrate 1 and IGF1R, in ErbB2-overexpressing breast cancer cells and mouse mammary tumor-derived tissues. Moreover, phenformin suppressed IGF1-stimulated proliferation, receptor tyrosine kinase signaling, and epithelial-mesenchymal transition markers in vitro. Together, our study implicates phenformin-mediated IGF1/IGF1R regulation as a potential anti-cancer mechanism and supports the development of phenformin and other biguanides as breast cancer therapeutics.
Highlights
Recent advances in cancer research suggest a link between metformin, a commonly prescribed antitype 2 diabetes drug, and reduced cancer risk, including prostate, lung, pancreatic, and breast cancer [1,2,3]
We found that phenformin significantly inhibits proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in ErbB2-overexpressing breast cancer cells and blocks tumor growth in a syngeneic mammary tumor model, which were associated with the inhibition of IGF1R stimulation
To further explore the role of IGF1R signaling pathway in the anti-cancer activity and EMT modulation of phenformin, we examined the specific effects of phenformin on IGF1-induced proliferation, receptor tyrosine kinase (RTK) signaling, and the alteration of EMT markers in SKBR3 and 78617 cells
Summary
Recent advances in cancer research suggest a link between metformin, a commonly prescribed antitype 2 diabetes drug, and reduced cancer risk, including prostate, lung, pancreatic, and breast cancer [1,2,3]. Results from animal models and cultured cell lines provide general support for the anti-cancer effects of metformin, despite inconsistent data in non-diabetic patients [4,5,6]. Metformin-mediated anti-cancer activities have been associated with both systemic and cellular regulatory activities, including lowering insulin levels, increasing insulin sensitivity, and activation of AMP-activated protein kinase (AMPK)/inhibition of mammalian target of rapamycin (mTOR) [3, 7]. It appears that metformininduced insulin receptor (IR) and insulin growth factor (IGF) receptor (IGFR) inactivation stimulates the regulatory network as well [8, 9]. In order www.impactjournals.com/oncotarget to further elucidate the anti-cancer potential of metformin, it is critical to investigate other biguanide drugs, such as phenformin
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