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

• Published in: PloS one 2017-05, Vol.12 (5), p.e0178454-e0178454
• Main Authors: Mishra, Ameet K, Parish, Christopher R, Wong, Ma-Li, Licinio, Julio, Blackburn, Anneke C
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adipocytes; Adipose tissue; Aging; Aging (artificial); American Type Culture Collection; AMP; AMP-activated protein kinase; Annexin V; Antibodies; Anticancer properties; Antitumor agents; Apoptosis; Apoptosis - physiology; Assaying; Attenuation; Binding energy; Biology; Biology and Life Sciences; Body fat; Body mass; Body mass index; Body weight; Brain; Breast - metabolism; Breast - physiology; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Care and treatment; Cell cycle; Cell death; Cell growth; Cell Line, Tumor; Cell Proliferation - physiology; Cholesterol; Complications and side effects; Computer programs; Culture media; Data acquisition; Documents; Drug resistance; Epithelial-Mesenchymal Transition - physiology; Estrogens; Female; Floating; Genetic aspects; Health risks; Heart diseases; Humans; Inhibition; Insulin; Interleukin 1; Interleukin 6; Kinases; Leptin - metabolism; Lung cancer; MCF-7 Cells; Medical research; Medicine; Medicine and Health Sciences; Metabolism; Mice; Mortality; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Obesity; Obesity - metabolism; Obesity - pathology; Physiological aspects; Physiological effects; Population studies; Prognosis; Proteins; Quality; Risk; Rodents; Signal Transduction - physiology; Stem cells; Tissues; Transforming Growth Factor beta1 - metabolism; Transforming growth factors; Tumor cells; Tumors; Weight reduction
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178454

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.