Oncogenic role and therapeutic target of leptin signaling in breast cancer and cancer stem cells

Abstract

Significant correlations between obesity and incidence of various cancers have been reported. Obesity, considered a mild inflammatory process, is characterized by a high level of secretion of several cytokines from adipose tissue. These molecules have disparate effects, which could be relevant to cancer development. Among the inflammatory molecules, leptin, mainly produced by adipose tissue and overexpressed with its receptor (Ob-R) in cancer cells is the most studied adipokine. Mutations of leptin or Ob-R genes associated with obesity or cancer are rarely found. However, leptin is an anti-apoptotic molecule in many cell types, and its central roles in obesity-related cancers are based on its pro-angiogenic, pro-inflammatory and mitogenic actions. Notably, these leptin actions are commonly reinforced through entangled crosstalk with multiple oncogenes, cytokines and growth factors. Leptin-induced signals comprise several pathways commonly triggered by many cytokines (i.e, canonical: JAK2/STAT; MAPK/ERK1/2 and PI-3K/AKT1 and, non-canonical signaling pathways: PKC, JNK and p38 MAP kinase). Each of these leptin-induced signals is essential to its biological effects on food intake, energy balance, adiposity, immune and endocrine systems, as well as oncogenesis. This review is mainly focused on the current knowledge of the oncogenic role of leptin in breast cancer. Additionally, leptin pro-angiogenic molecular mechanisms and its potential role in breast cancer stem cells will be reviewed. Strict biunivocal binding-affinity and activation of leptin/Ob-R complex makes it a unique molecular target for prevention and treatment of breast cancer, particularly in obesity contexts.

Favorable Changes in Serum Estrogens and Other Biologic Factors After Weight Loss in Breast Cancer Survivors Who are Overweight or Obese

“…36, 37 Adipocytes secrete leptin and other adipokines, and leptin concentration is positively correlated with total adipose tissue. 38 Although it can be challenging to separate the effects of leptin from other adipokines, some studies have shown leptin levels to have independent prognostic effects on breast cancer.…”

Obesity, Inflammation, and Cancer

“…Conversely, increases in leptin both induce aromatase-mediated estrogen production and transactivate ER signaling in MCF7 breast cancer cells, as well as stimulate leukocyte secretion of IL-1, IL-6, IL-12, TNFα, IFNγ, and nitric oxide, which may create a regulatory feedback cascade to promote tumor growth and leukocyte invasion. Leptin can also increase tumor production of several proangiogenic factors, including MMP-2, MMP-9, and VEGF, although leptin has itself been reported to promote angiogenesis through actions on VEGF receptor signaling and Notch expression (101,102). Finally, recent studies suggest that leptin may promote breast cancer epithelial-mesenchymal transition and cancer stem cell renewal (101,103).…”

Activation of IL-8 via PI3K/Akt-dependent pathway is involved in leptin-mediated epithelial-mesenchymal transition in human breast cancer cells

“…Binding to the specific receptors (Ob-R) is essential for leptin to execute its biological functions (23). Western blot and Immunofluorescence assay were performed to examine the expression of of ObR, Leptin and IL-8 in invasive breast carcinoma without axillary lymph node metastases was lower than those in LNM，and higher than those in benign breast tissue.…”