Adipocytes induce distinct gene expression profiles in mammary tumor cells and enhance inflammatory signaling in invasive breast cancer cells

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.

Adipocytes and Obesity-Related Conditions Jointly Promote Breast Cancer Cell Growth and Motility: Associations With CAP1 for Prognosis

“…Contrary to the growth promoting responses, the low proliferative and epithelial-like T47D cells demonstrated the most pronounced morphological alterations with increased abundance of stellate protrusion and activation of motility in response to adipocytes and obesity-associated metabolic conditions, followed by the more proliferative MCF-7 or triple-negative MDA-MB-231 cells. Although our models showed the most pronounced induction of migration in the two low-invasive ER + cells, others have demonstrated a significant role of the adipose microenvironment in facilitating also triple-negative breast cancer cell motility and invasiveness ( 30 – 32 ). Co-culture with 3T3-L1 adipocytes may induce a similar yet a more marked response in breast cancer cells compared to that induced by adipocyte secretome alone, due to the continuous exchange of soluble mediators ( 32 ).…”

“…Although our models showed the most pronounced induction of migration in the two low-invasive ER + cells, others have demonstrated a significant role of the adipose microenvironment in facilitating also triple-negative breast cancer cell motility and invasiveness ( 30 – 32 ). Co-culture with 3T3-L1 adipocytes may induce a similar yet a more marked response in breast cancer cells compared to that induced by adipocyte secretome alone, due to the continuous exchange of soluble mediators ( 32 ). This may in part explain the difference in magnitude of response between studies.…”

Active Behavior of Triple-negative Breast Cancer With Adipose Tissue Invasion: A Single Center and Retrospective Review

“…Indeed, adipocytes are considered to constitute a critical cell type in the tumor microenvironment of BC 17,18 . Recently, moreover, some investigators highlighted the striking effects of adipocytes on the human TNBC cell line, that is, enhanced cell migration and invasion 19 . In the present study, it is suggested that nodal status is a very strong prognostic factor in TNBC.…”

The Spatial and Genomic Hierarchy of Tumor Ecosystems Revealed by Single-Cell Technologies

“…There is a high degree of spatial correlation within tumors because cells with similar phenotypic profiles are often contained within similar microenvironments. The phenotypic diversity of cells is shaped by diverse gradients, including those formed by systemic hormones, local diffusible factors such as TGF-β [58] and Wnt [59], as well as variable nutrient and environmental cues [6], and unknown factors that promote proliferation of cells in close proximity to adipocytes [60]. Furthermore, the heterogeneous tumor immune microenvironment substantially impacts intratumoral diversity and evolution [19] (see Box 1).…”