Despite numerous epidemiological data linking type 2 diabetes mellitus (T2DM) and breast cancer (BCa), there is limited experimental evidence of this association. The clinically relevant question is at what stage diabetes may exert its tumor-promoting activity. Moreover, identification of major pathophysiological pathways underlying this activity should provide valuable information for treatment. In the present study, the BCa cells isolated from long-term T2DM-treated tumors from diabetic nude mice were found to have increased cell proliferation, invasiveness and docetaxel (DTX) resistance. Importantly, this stimulatory effect was only observable in estrogen receptor (ER)-positive BCa cells. Mechanistically, T2DM-elicited hyperinsulinemia induced HIF-1α expression by reducing its ubiquitination, which was accompanied with upregulated oxidative stress. Furthermore, in vivo inhibition of HIF-1α expression effectively reversed the above-mentioned tumor-promoting activity and partially attenuated T2DM-elicited oxidative stress. Altogether, the results provide novel and compelling experimental evidence that (i) prolonged exposure to T2DM promotes BCa progression; (ii) the hyperinsulinemia/HIF-1α/oxidative stress cascade is the major mediator of this effect.
Keywords: Breast cancer; HIF-1α; Hyperinsulinemia; Oxidative stress; Type 2 diabetes mellitus.
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