Obesity increases the risk of breast cancer death in postmenopausal women with estrogen receptor (ER)-positive breast cancer, although underlying mechanisms remain unclear. In studies reported in the Journal of the National Cancer Institute, Fuentes-Mattei and colleagues identified an association of obesity with 59 biologic functional changes (P < .05) linked to cancer hallmarks using functional transcriptomic analysis in pretreatment biopsies from a prospective cohort of 137 ER-positive breast cancer patients. Gene enrichment analysis showed significant enrichment of AKT target genes (P = .04) and epithelial-mesenchymal transition genes (P = .03).
Investigation in obese mouse models showed activation of the AKT/mTOR pathway in obesity-accelerated mammary tumor growth (3.7- to 7.0-fold, P < .001). Treatment with metformin or everolimus (Afinitor) suppressed obesity-induced secretion of adipokines and breast tumor formation and growth (0.5-fold, P = .04; 0.3-fold, P < .001).
In a coculture model examining the impact of adipocytes/adipokines on breast cancer cell proliferation, adipocyte-secreted adipokines (eg, TIMP-1) regulated adipocyte-induced proliferation and invasion. Metformin suppressed the adipocyte-induced cell proliferation and adipokine secretion from adipocytes.
The investigators concluded, “Adipokine secretion and AKT/mTOR activation play important roles in obesity-accelerated breast cancer aggressiveness in addition to hyperinsulinemia, estrogen signaling, and inflammation. Metformin and everolimus have potential for therapeutic interventions of ER[-positive] breast cancer patients with obesity.” ■
Fuentes-Mattei E, et al: J Natl Cancer Inst 106(7):dju158, 2014.