Leptin induces cell migration and invasion in a FAK-Src-dependent manner in breast cancer cells.

Breast cancer is the most common invasive neoplasia, and the second leading cause of the cancer deaths in women worldwide. Mammary tumorigenesis is severely linked to obesity, one potential connection is leptin. Leptin is a hormone secreted by adipocytes, which contributes to the progression of breast cancer. Cell migration, metalloproteases secretion, and invasion are cellular processes associated with various stages of metastasis. These processes are regulated by the kinases FAK and Src. In this study, we utilized the breast cancer cell lines MCF7 and MDA-MB-231 to determine the effect of leptin on FAK and Src kinases activation, cell migration, metalloprotease secretion, and invasion. We found that leptin activates FAK and Src and induces the localization of FAK to the focal adhesions. Interestingly, leptin promotes the activation of FAK through a Src- and STAT3-dependent canonical pathway. Specific inhibitors of FAK, Src and STAT3 showed that the effect exerted by leptin in cell migration in breast cancer cells is dependent on these proteins. Moreover, we established that leptin promotes the secretion of the extracellular matrix remodelers, MMP-2 and MMP-9 and invasion in a FAK and Src-dependent manner. Our findings strongly suggest that leptin promotes the development of a more aggressive invasive phenotype in mammary cancer cells.

Extracellular-Signal Regulated Kinase: A Central Molecule Driving Epithelial-Mesenchymal Transition in Cancer.

Epithelial-mesenchymal transition (EMT) is a reversible cellular process, characterized by changes in gene expression and activation of proteins, favoring the trans-differentiation of the epithelial phenotype to a mesenchymal phenotype. This process increases cell migration and invasion of tumor cells, progression of the cell cycle, and resistance to apoptosis and chemotherapy, all of which support tumor progression. One of the signaling pathways involved in tumor progression is the MAPK pathway. Within this family, the ERK subfamily of proteins is known for its contributions to EMT. The ERK subfamily is divided into typical (ERK 1/2/5), and atypical (ERK 3/4/7/8) members. These kinases are overexpressed and hyperactive in various types of cancer. They regulate diverse cellular processes such as proliferation, migration, metastasis, resistance to chemotherapy, and EMT. In this context, in vitro and in vivo assays, as well as studies in human patients, have shown that ERK favors the expression, function, and subcellular relocalization of various proteins that regulate EMT, thus promoting tumor progression. In this review, we discuss the mechanistic roles of the ERK subfamily members in EMT and tumor progression in diverse biological systems.

Leptin induces partial epithelial-mesenchymal transition in a FAK-ERK dependent pathway in MCF10A mammary non-tumorigenic cells.

Epithelial-mesenchymal transition (EMT) is a biological process involved in different steps of tumor progression and metastasis of breast cancer cells. Epidemiological studies suggest a link between obesity and the progression of breast cancer. Leptin is an adipocyte-secreted hormone which can promote cell migration and invasion as part of EMT in breast cancer cells. We investigated the effect of leptin on expression of EMT markers in MCF10A cells, as well as, the role of FAK and ERK in this process. We found that leptin induces morphological changes from an epithelial phenotype towards a mesenchymal phenotype and promotes cell migration in MCF10A cells. Moreover, leptin induces an increase in vimentin expression, changes in the cellular localization of E-cadherin and increase in FAK and ERK phosphorylation. Furthermore, using FAK and ERK chemical inhibitors we show that leptin regulates EMT markers in a FAK and ERK dependent manner. In conclusion, leptin promotes vimentin expression and cell migration in a FAK and ERK dependent pathway in the non-tumorigenic epithelial cell line MCF10A.