Multifaceted Leptin Network: The Molecular Connection Between Obesity and Breast Cancer

Abstract

High plasma levels of leptin, a major adipocytokine produced by adipocytes, are correlated with increased fat mass in obese state. Leptin is emerging as a key candidate molecule linking obesity with breast cancer. Acting via endocrine, paracrine, and autocrine manner, leptin impacts various stages of breast tumorigenesis from initiation and primary tumor growth to metastatic progression. Leptin also modulates the tumor microenvironment mainly through supporting migration of endothelial cells, neo-angiogenesis and sustaining recruitment of macrophage and monocytes. Various studies have shown that hyperactive leptin-signaling network leads to concurrent activation of multiple oncogenic pathways resulting in enhanced proliferation, decreased apoptosis, acquisition of mesenchymal phenotype, potentiated migration and enhanced invasion potential of tumor cells. Furthermore, the capability of leptin to interact with other molecular effectors of obese state including, estrogen, IGF-1, insulin, VEGF and inflammatory cytokines further increases its impact on breast tumor progression in obese state. This article presents an overview of the studies investigating the involvement of leptin in breast cancer.

Lunasin Attenuates Obesity-Associated Metastasis of 4T1 Breast Cancer Cell through Anti-Inflammatory Property

“…In obese subjects, increasing levels of circulating VEGF accompanied tumoral expression, which was linked to cancer patients with a poor prognosis [12,27]. This increase of VEGF was also shown in the tumors of obese mice [20]; several inflammatory adipokines, which were increased with obesity, contributed to breast carcinogenesis [21].…”

Obesity and cancer: inflammation bridges the two

“…As mentioned above, obesity-associated metabolic syndrome and elevated insulin levels are tightly linked with inflammation [25]. Leptin is also known to induce the expression of pro-inflammatory, pro-tumorigenic cytokines in macrophages, including IL-1, IL-6 and TNF-α [59]. Other studies have shown the concomitant elevation of IL-1β and leptin with increased body mass in rats that drives the growth of mammary epithelium [60] and that leptin expression in pre-adipocytes can be induced by IL-1 and TNF-α secreted from ATM [61].…”

Obesity and Breast Cancer: Adipose Tissue, Adipocytokines, Chronic Inflammation, and Hypoxia

“…Leptin is the most important weight controlling adipokine in white fat tissue and thus has a key role in the relationship between obesity and cancer. It is reported to affect survival, migration, and growth of cancer cells by increasing the expression of antiapoptotic proteins; estrogen; pro-inflammatory cytokines, such as TNF-α and IL-6; and angiogenic factors, such as VEGF and hypoxia-induced factors (HIF-1α) (18,19,(71)(72)(73)(74). In a cell culture study that investigated the effect of leptin on breast cancer, leptin (obASC) from obese patients led to increased proliferation of ER-positive breast cancer cells, whereas no such effect was observed in case of leptin (InASC) from patients with BMI less than 25 kg/m 2 .…”

“…The ranking for all groups was as follows: healthy control, control with light breast disease, patients with breast cancer, and patients with lymph node metastasis. Serum leptin levels in postmenopausal ER-positive breast cancer patients were found to be the lowest in clinical and pathologic classifications (72,73,76). Increased ectopic lipoaccumulation in obesity leads to tissue hypoxia, inflammation, and reactive angiogenesis, leading to changes in tumorigenesis and tumor characteristics (metastasis, invasion) (77).…”