Leptin signals via TGFB1 to promote metastatic potential and stemness in breast cancer

Abstract

Epidemiological studies have shown obesity to be linked with poorer outcomes in breast cancer patients. The molecular mechanisms responsible for the increased risk of invasive/metastatic disease with obesity are complex, but may include elevated levels of adipokines such as leptin. Using physiological levels of leptin found in obesity in a novel chronic in vitro treatment model (≤200 ng/ml for 14 days), we confirmed the occurrence of leptin-mediated changes in growth, apoptosis and metastatic behavior, and gene expression changes representing epithelial-to-mesenchymal transition (EMT) and a cancer stem cell (CSC) like phenotype in breast epithelial and cancer cell lines (MCF10A, MCF10AT1, MCF7 and MDA-MB-231). Further, we have discovered that these effects were accompanied by increased expression of TGFB1, and could be significantly reduced by co-treatment with neutralizing antibody against TGFB1, indicating that the induction of these characteristics was mediated via TGFB1. Occurring in both MCF7 and MCF10AT1 cells, it suggests these actions of leptin to be independent of estrogen receptor status. By linking leptin signalling to the established TGFB1 pathway of metastasis / EMT, this study gives a direct mechanism by which leptin can contribute to the poorer outcomes of obese cancer patients. Inhibitors of TGFB1 are in currently in phase III clinical trials in other malignancies, thus identifying the connection between leptin and TGFB1 will open new therapeutic opportunities for improving outcomes for obese breast cancer patients.

Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer

“…TGFB1 binds the TGFB receptor, leading to the phosphorylation and nuclear translocation of SMAD2 and SMAD3, which mediate proliferation, differentiation, migration and cancer stemness by binding to transcription factors such as SMAD4 . TGFB1 suppresses oncogenesis by regulating proliferation, although it promotes cancer progression by contributing to invasion and metastasis of established tumors . Evidence indicates that TGFB1 mediates tumor progression in concert with FRAS1, because FRAS1 is expressed in cancer tissues.…”

“…35 TGFB1 suppresses oncogenesis by regulating proliferation, although it promotes cancer progression by contributing to invasion and metastasis of established tumors. 36 Evidence indicates that TGFB1 mediates tumor progression in concert with FRAS1, because FRAS1 is expressed in cancer tissues. AHNAK is associated with tumor progression 37 or suppression and increases signaling through the TGFB pathway.…”

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

“…-catenin can be relocated into the nucleus where acts as a transcription factor forming complexes with DNA binding proteins such as TCF/LEF [89,90]. In this study, we observed that β-catenin expression increases in leptin-stimulated cells in addition to a nuclear relocation of β-catenin at 3 h. These findings might be related to the decrease in the expression or changes in the location of proteins at adherent junctions, particularly, Ecadherin and β-catenin plays an important role in the induction of EMT [91].…”

Translational opportunities for broad‐spectrum natural phytochemicals and targeted agent combinations in breast cancer

“…73 Leptin induces TGFb1 expression, decreases the epithelial marker Ecadherin and increases EMT marker SNAI2 in BC cells. 74 In addition, leptin increases the CD44 1 /CD24 2 stem cell population in BC cells. 75 HER2 and leptin have mutual inductive effects and leptin decreases the sensitivity to anti-HER2 interventions in HER2 1 BC.…”

“…Interestingly, many breast tumors also express leptin receptors which are positively associated with BC proliferation . Leptin induces TGFβ1 expression, decreases the epithelial marker E‐cadherin and increases EMT marker SNAI2 in BC cells . In addition, leptin increases the CD44 + /CD24 − stem cell population in BC cells .…”