Control of breast cancer cell growth by adipocyte-released factors.

Obesity is one of the most challenging and growing health problems, worldwide. Epidemiologic studies now provide compelling evidence that obesity is a risk factor for both cancer incidence and mortality. In particular, obesity increases rates of breast cancer in postmenopausal women and is associated with poorer survival and increased recurrence of disease, regardless the menopausal status. It is now becoming clear that adipocytes, which represent very abundant cell types surrounding cancer cells, particularly in the mammary gland, could influence several aspects of tumorigenesis, from promoting local invasion to angiogenesis and metastasis. However, the molecular mechanisms involved in the adipocyte control of the malignant phenotype remain poorly understood. I have studied the mechanisms by which adipocytes may integrate metabolic and nutritional inputs and produce signals affecting breast cancer cell phenotypes. I have obtained evidence that conditioned media from 3T3-L1 cells induce growth of MCF7 cells, in a time-dependent manner. In particular, conditioned media from fully differentiated adipocytes are 2-fold more effective than conditioned media from pre-adipocytes in inducing MCF7 growth. Cell cycle analysis by flow cytometry revealed that these changes are due to reduced apoptosis instead of increased proliferation. Pre-incubation with low glucose medium or insulin reduces the effect of adipocyte conditioned media on MCF7 growth. Cytokines/growth factors screening of conditioned media from pre-adipoctyte and adipocyte, cultured in presence or in absence of low glucose medium or insulin, revealed that KC, RANTES and IGF1 could be good candidates in mediating pro-tumorigenic effect of adipocyte conditioned media. Moreover, IGF1R inhibitor AG1024 is able to revert adipocyte conditioned media effect. In conclusion, adipocyte-derived factors promote breast cancer cell growth inhibiting the apoptosis. This effect is more evident in adipocytes than in pre-adipocytes and is altered by insulin or nutritional factors such as glucose. The effects are likely mediated by IGF-1