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.
Highlights
Breast cancer is the second-leading cause of cancer-related deaths among women worldwide [1]
We have examined the effect of chronic, physiological leptin treatment on the metastatic and cancer stem cell (CSC)-like characteristics of breast epithelial and cancer cells, and have discovered that promotion of invasiveness and CSC behavior by leptin is mediated through binding of TGFB1 to its receptor, increasing the likely contribution of leptin signalling to poorer outcomes in obesity, and adding to the list of pathways that may be readily targeted in obese cancer patients
MCF10A and MCF10AT1 cells did not differ in LEPR mRNA expression, whereas higher expression of LEPR mRNA (Fig 1A) was found in MDA-MB-231 compared to MCF7 cells
Summary
Breast cancer is the second-leading cause of cancer-related deaths among women worldwide [1]. Obesity is linked with many aspects of breast cancer including higher prevalence, higher grade tumors, higher rates of metastatic, recurrent, or drug resistant disease, and higher relative risk of death [4,5,6,7]. Cancer associated adipocytes are the source of a number of secreted factors including leptin, IL6, IL1β and estrogen, and these factors have been independently linked with breast cancer progression [12]. Numerous studies have previously shown that leptin can directly act on breast cancer cells and modulate their behavior, including promoting proliferation, transformation and reducing apoptosis (reviewed in [21]), the effect of leptin on the metastatic process is relatively poorly understood
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