Background: Epidemiological studies from us and others have reported an association of obesity with more aggressive breast tumors and >30% higher risk of recurrence and mortality compared to normal weight patients. This includes poorer outcomes for triple negative breast cancer (TNBC), an aggressive subtype with early recurrence and shorter survival. Metformin is a leading frontline therapy for type 2 diabetes and its safety profile is well documented. Laboratory and clinical studies including ours suggest that metformin may have anti-tumor effects in breast cancer. However, the nature and molecular mechanisms of these correlations are poorly understood.

Experimental design and methods: We used a PDX (patient-derived xenograft) breast cancer model in diet-induced obese mice to study how obesity promotes breast cancer growth and how metformin antagonizes these effects. After feeding the mice with a high-fat diet (HFD) vs. a control diet (CD), we transplanted a TNBC PDX into the mammary fat pads. When tumors reached about 50 mm3, mice in HFD and CD groups were randomly assigned to metformin treatment or no treatment. Tumor volumes were measured bi-weekly, and blood, tumors, and organs were collected after 4 weeks of treatment. Histological and immunohistochemical staining, serum adipokines array and metabolomics and lipidomics analyses were performed to examine potential mechanisms.

Results: HFD (obese) group compared to CD (lean) group was associated with larger tumors, whereas metformin compared to no treatment was associated with smaller tumors. A panel of adipokines and metabolites was identified to be differentially expressed between the groups.

Conclusion: Our results suggest a growth promoting effect of obesity in TNBC, while metformin appears to have the opposite effect. The identification of adipokines and metabolites involved in these effects will help us understand the mechanisms by which obesity and metformin alter the progression of TNBC.

Citation Format: Laura Camacho, Lei Xue, Lacey Dobrolecki, Susan G. Hilsenbeck, Chandandeep Nagi, Nagireddy Putluri, Michael T. Lewis, Arun Sreekumar, Sao Jiralerspong. Obesity and metformin alter progression of triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3470.