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Advanced glycation end products (AGEs) and the cognate receptor, named RAGE, are involved in metabolic disorders characterized by hyperglycemia, type 2 diabetes mellitus (T2DM) and obesity. Moreover, the AGEs/RAGE transduction pathway prompts a dysfunctional interaction between breast cancer cells and tumor stroma toward the acquisition of malignant features. However, the action of the AGEs/RAGE axis in the main players of the tumor microenvironment, named breast cancer-associated fibroblasts (CAFs), remains to be fully explored. In the present study, by chemokine array, we first assessed that interleukin-8 (IL-8) is the most up-regulated pro-inflammatory chemokine upon AGEs/RAGE activation in primary CAFs, obtained from breast tumors. Thereafter, we ascertained that the AGEs/RAGE signaling promotes a network cascade in CAFs, leading to the c-Fos-dependent regulation of IL-8. Next, using a conditioned medium from AGEs-exposed CAFs, we determined that IL-8/CXCR1/2 paracrine activation induces the acquisition of migratory and invasive features in MDA-MB-231 breast cancer cells. Altogether, our data provide new insights on the involvement of IL-8 in the AGEs/RAGE transduction pathway among the intricate connections linking breast cancer cells to the surrounding stroma. Hence, our findings may pave the way for further investigations to define the role of IL-8 as useful target for the better management of breast cancer patients exhibiting metabolic disorders. [ABSTRACT FROM AUTHOR]

Metabolic disorders, such as obesity, type 2 diabetes (T2D) and metabolic syndrome, have been implicated in breast cancer (BC) progression. In this regard, insulin has been shown to promote mitogenic and metastatic responses in BC through diverse signaling pathways. Moreover, high levels of insulin and elevated expression of its cognate receptor, namely insulin receptor (IR), have been associated with increased BC incidence, resistance to treatments and poor outcomes. Metformin (1,1-dimethylbiguanide hydrochloride) is the most commonly prescribed drug for T2D treatment worldwide. Metformin has been shown to interfere with BC cell growth. In order to provide novel insights through which metformin can elicit anti-cancer responses in BC, we performed bioinformatics analysis as well as TaqMan Gene Expression Assay, flow cytometry, immunofluorescence, immunoblots, 2D and 3D proliferation assays and motility experiments. A naturally immortalized BC cell line (namely BCAHC-1) and important components of the tumor microenvironment, such as cancer-associated fibroblasts (CAFs) derived from BC patients, were used as model systems. We found that metformin inhibits the activation of main transduction pathways, the gene expression changes and the proliferative effects induced by insulin in BCAHC-1 cells. Moreover, metformin prevented the insulin-stimulated induction of CXC chemokine receptor 4 (CXCR4), which has been involved in BC metastatic dissemination. Next, metformin suppressed the invasion of CAFs triggered through CXCR4 via insulin stimulated BCAHC-1 cells. Our findings may suggest novel transduction mechanisms involved in the inhibitory effects elicited by metformin in both BC cells and CAFs. [ABSTRACT FROM AUTHOR]