Leptin signaling in breast cancer: An overview

Abstract

The adipocyte-derived peptide leptin acts through binding to specific membrane receptors, of which six isoforms (obRa-f) have been identified up to now. Binding of leptin to its receptor induces activation of different signaling pathways, including the JAK/STAT, MAPK, IRS1, and SOCS3 signaling pathways. Since the circulating levels of leptin are elevated in obese individuals, and excess body weight has been shown to increase breast cancer risk in postmenopausal women, several studies addressed the role of leptin in breast cancer. Expression of leptin and its receptors has been demonstrated to occur in breast cancer cell lines and in human primary breast carcinoma. Leptin is able to induce the growth of breast cancer cells through activation of the Jak/STAT3, ERK1/2, and/or PI3K pathways, and can mediate angiogenesis by inducing the expression of vascular endothelial growth factor (VEGF). In addition, leptin induces transactivation of ErbB-2, and interacts in triple negative breast cancer cells with insulin like growth factor-1 (IGF-1) to transactivate the epidermal growth factor receptor (EGFR), thus promoting invasion and migration. Leptin can also affect the growth of estrogen receptor (ER)-positive breast cancer cells, by stimulating aromatase expression and thereby increasing estrogen levels through the aromatization of androgens, and by inducing MAPK-dependent activation of ER. Taken together, these findings suggest that the leptin system might play an important role in breast cancer pathogenesis and progression, and that it might represent a novel target for therapeutic intervention in breast cancer.

High expression of leptin receptor leads to temozolomide resistance with exhibiting stem/progenitor cell features in gliobalastoma

“…Furthermore, ObR had full signaling capabilities and was able to activate the JAK/STAT3 pathway, the major pathway used by leptin to exert its effects. 20 In our study, both ObR+ cells and U87R cells exhibited active STAT3 and increased levels of SOX2 and OCT4, when STAT3 activity was inhibited, the pluripotency-associated transcription factors were downregulated. Additionally, the self-reinforcing leptin-signaling module active within ObR+ cells resulted in maintaining cells self-renewal and malignancy.…”

“…19 Among the adipokines, leptin is the most intensively studied factor due to its involvement in tumor initiation, primary tumor growth, invasion, and metastasis. 20 However leptin contributes to cancer initiation or whether its role is restricted to promoting the growth of existing tumor cells may primarily depend on receptor levels of ObR among those cells. 13 Diverse cancer cells derived from different tissues, such as brain, breast, colon or prostate, were reported to have ObR expression.…”

Leptin accelerates enterocyte turnover during methotrexate-induced intestinal mucositis in a rat model

“…Leptin serum levels are about five times higher in obese people than in normal individuals. Leptin has been reported to act as a mitogenic agent and stimulates the growth of several obesity-associated advanced human cancers, including breast cancer, 25 colon cancer, 26 endometrial cancer 27 and renal cancer. 28 The use of leptin in these patients to prevent chemotherapy-induced mucositis should be probably avoided.…”

Adipose tissue, obesity and adipokines: role in cancer promotion

“…Leptin is proposed to act initially on breast epithelial cells, transforming them into malignant forms that affect surrounding cells in a paracrine fashion to mediate further cancer cell proliferation [39]. Moreover, addition of leptin to MCF-7 breast cancer cells decreases the expression of the cancer suppression protein p53, exploiting cancer cell survival property [40].…”