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

Abstract

Breast cancer is the most common invasive neoplasia, and the second leading cause of death associated with cancer in women worldwide. Mammary tumorigenesis is severely linked to obesity, the 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-231to determine the effect of leptin on FAK and Src kinases activation, cell migration, metalloproteases secretion, and invasion. By Western blot we found that leptin activates FAK and Src, and induces the localization of FAK to the focal adhesions. Specific inhibitors of FAK and Src showed that the effect exerted by leptin in cell migration, and invasion in breast cancer cells is dependent on these kinases. Moreover, by gelatin zymmography we established that leptin promotes the secretion of the extracellular matrix remodelers, MMP-2 and MMP-9, 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.

Leptin promotes expression of EMT-related transcription factors and invasion in a Src and FAK-dependent pathway in MCF10A mammary epithelial cells

“…Our results showed early maximal activation peaks for both kinases within 10-15 min of leptin stimulation. These data is consistent with our previous report, where leptin induced the activation of FAK between 10-30 min of stimulation in MCF10A, MCF7 and MDA-MB-231 cells [43,51]. However, the mechanism by which leptin activates Src and FAK in MCF10A remain unclear, and several alternatives should be explored in the future.…”

“…Kinase activation is a fundamental process for cancer progression and metastasis [49,50]. Src and FAK activation is triggered by the autophosphorylation at Y418 and Y397, respectively [49,51,52]. Emerging evidence from our lab and others showed that these kinases may also contribute to early events during EMT [53][54][55][56].…”

“…Twist and β-catenin are downstream effectors of different kinases and signaling pathways [24]. We focused on the effect of Src and FAK in the activation of these TFs, as both kinases are associated to EMT-related events [15,43,51]. To address this, we took advantage of the specific Src and FAK inhibitors, PP2 or PF-573228, respectively.…”

“…The remodeling of actin filaments during EMT is essential necessary [67]. Our group and others have shown that during leptin-induced EMT of MCF10A cells [43], and in several cancer cell lines [51,68,69], this hormone promotes the formation of stress fibers [70,71]. However, understanding of how this process is regulated is still limited.…”

Three‐dimensional culture models to study drug resistance in breast cancer

“…The MCF‐7 or BT474 breast cancer cells cultured in the model displayed increased resistance to DOX driven by increased activity of focal adhesion kinase (FAK) due to breast cancer cell interaction with the collagen I and fibronectin CAF‐derived ECM (Nayak et al, 2019). FAK is known to activate pro‐survival pathways which further cancer progression (Juarez‐Cruz et al, 2019).…”