Signaling Pathways Induced by Leptin during Epithelial–Mesenchymal Transition in Breast Cancer

Abstract

Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial–mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell–cell and cell–extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides cells with the ability to migrate and invade adjacent or distal tissues, which is a classic feature of invasive or metastatic carcinoma cells. In recent years, the number of cases of breast cancer has increased, making this disease a public health problem worldwide and the leading cause of death due to cancer in women. In this review, we focus on recent advances that establish: (1) leptin as a risk factor for the development of breast cancer, and (2) leptin as an inducer of EMT, an event that promotes tumor progression.

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

“…EMT is a reversible cellular process by which epithelial cells undergo trans-differentiation events from an epithelial to a mesenchymal phenotype in where EMT-related transcription factors are key molecules [3]. EMT is also associated with tumor progression and the invasive and metastatic phenotype in cancer cells [14].…”

“…Leptin is a 16 kDa hormone secreted mainly by adipose tissue, and in lesser extent by the placenta, stomach, fibroblasts, skeletal muscle, normal and tumorigenic mammary epithelial tissue [1]. Leptin plays an important role in the regulation of energy homeostasis, endocrine and immune functions, as well as in lipid and glycolytic metabolism [2,3]. The overexpression of leptin and its receptor, the ObR, has been associated to tumor progressionrelated events in breast cancer [4][5][6].…”

“…The overexpression of leptin and its receptor, the ObR, has been associated to tumor progressionrelated events in breast cancer [4][5][6]. Leptin exerts its effects through binding with the ObR receptor, promoting the activation of several signaling pathways such as MAPK, PI3K/AKT and JAK/STAT [3,7,8]. The signaling pathways activated by leptin regulate cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) [4,5,[9][10][11].…”

“…EMT is a physiological process necessary for embryonic development, wound healing and tissue regeneration; however, it is also associated with cancer progression [12,13]. At molecular level, EMT is characterized by the loss of epithelial markers such as E-cadherin, ZO-1, claudins, and acquisition of mesenchymal markers including N-cadherin, vimentin, Hic-5 and matrix metalloproteases (MMPs) [3,15]. To initiate the EMT program, signals are required that activate specific transcription factors (TFs) such as Snail, Slug, Zeb and Twist [13].…”

“…Overexpression of these TFs in epithelial cells induces either partial or complete changes from an epithelial to mesenchymal morphology, associated with increased motility, invasive capacity and resistance to chemotherapy [17][18][19]. In normal conditions, the epithelial cells maintains adherent junctions, where E-cadherin forms a complex with βcatenin in the cell membrane [3,20]. During the EMT β-catenin translocates from the membrane to the nucleus where it establishes a complex with the TFs TCF/LEF.…”