Impact of diabetes on promoting the growth of breast cancer

Abstract

Background: Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.

Methods: We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2⁺ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Lepr^db/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.

Results: Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^db/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ¹³ C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Lepr^db/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.

Conclusions: MMTV-ErbB2/Lepr^db/db mouse model was able to recapitulate diabetic HER2⁺ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2⁺ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.

Keywords: breast cancer; diabetes; human epidermal growth factor receptor 2; metabolism; metformin.