Abstract
Obesity is a known risk factor for breast cancer. Since obesity rates are constantly rising worldwide, understanding the molecular details of the interaction between adipose tissue and breast tumors becomes an urgent task. To investigate potential molecular changes in breast cancer cells induced by co-existing adipocytes, we used a co-culture system of different breast cancer cell lines (MCF-7 and T47D: ER+/PR+/HER2− and MDA-MB-231: ER−/PR−/HER2−) and murine 3T3-L1 adipocytes. Here, we report that co-culture with adipocytes revealed distinct changes in global gene expression pattern in the different breast cancer cell lines. Our microarray data revealed that in both ER+ cell lines, top upregulated genes showed significant enrichment for hormone receptor target genes. In triple-negative MDA-MB-231 cells, co-culture with adipocytes led to the induction of pro-inflammatory genes, mainly involving genes of the Nf-κB signaling pathway. Moreover, co-cultured MDA-MB-231 cells showed increased secretion of the pro-inflammatory interleukins IL-6 and IL-8. Using a specific NF-κB inhibitor, these effects were significantly decreased. Finally, migratory capacities were significantly increased in triple-negative breast cancer cells upon co-culture with adipocytes, indicating an enhanced aggressive cell phenotype. Together, our studies illustrate that factors secreted by adipocytes have a significant impact on the molecular biology of breast cancer cells.
Highlights
The worldwide rising incidence of obesity poses a great burden to health care practitioners and the global health system
To identify genes and underlying pathways in human breast cancer cells affected by interaction with mature adipocytes, two estrogen-receptor positive (ER+) breast cancer cell lines, MCF-7 and T47D, and the triple-negative (TN) breast cancer cell line MDA-MB-231 were co-cultivated with or without differentiated 3T3-L1 cells for the purpose of a microarray gene expression analysis
Despite a growing body of evidence underlining the important role of obesity and excess adipose tissue in survival and growth of breast tumors, detailed knowledge about the molecular mechanisms linking adipocytes to tumor growth, survival, and metastasis is limited
Summary
The worldwide rising incidence of obesity poses a great burden to health care practitioners and the global health system. Several recent studies demonstrated that breast cancer cells and neighbouring adipocytes of the tumoral stroma interact with each other directly[6,12] This interaction leads to adipocytes with an activated, tumor supportive phenotype characterized by lipolysis, a decrease in adipocyte markers and an overexpression of pro-inflammatory cytokines like IL-6 and IL-1β. These so called cancer-associated adipocytes (CAA) contribute to the local inflammation and deliver energy for cell proliferation[13,14]. We highlight the striking effects of adipocytes on triple negative breast cancer cells, which show a significant induction of pro-inflammatory genes and pathways upon co-culture in addition to an enhanced ability of cell migration and invasion
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