Cellular and molecular crosstalk between leptin receptor and estrogen receptor-α in breast cancer: molecular basis for a novel therapeutic setting

Abstract

Obesity is associated with an increased risk of breast cancer. A number of adipocytokines are increased in obesity causing low-level chronic inflammation associated with an increased risk of tumors. The adipocytokine leptin shows profound anti-obesity and pro-inflammatory activities. We have hypothesized that in common obesity, high circulating leptin levels might contribute to an increased risk of breast cancer by affecting mammary cell proliferation and survival. Leptin exerts its activity not only through leptin receptor (LepR), but also through crosstalk with other signaling systems implicated in tumorigenesis. In this study, we focused our attention on the relationship between the leptin/LepR axis and the estrogen receptor-a (ERa). To this aim, we utilized two human breast cancer cell lines, one ERa-positive cell line (MCF 7) and the other ERa-negative cell line (MDA-MB 231). We observed that the two cell lines had a different sensitivity to recombinant leptin (rleptin): on MCF 7 cells, rleptin induced a strong phosphorylation of the signal transducer and activator of transcription (STAT) 3 and of the extracellular related kinase 1/2 pathways with an increased cell viability and proliferation associated with an increased expression of ERa receptor. This response was not present in the MDA-MB 231 cells. The effects induced by leptin were lost when LepR was neutralized using either a monoclonal inhibitory antibody to LepR or LepR genesilencing siRNA. These data suggest that there is a bidirectional communication between LepR and ERa, and that neutralization and/or inactivation of LepR inhibits proliferation and viability of human breast cancer cell lines. This evidence was confirmed by ex vivo studies, in which we analyzed 33 patients with breast cancer at different stages of disease, and observed that there was a statistically significant correlation between the expression of LepR and ERa. In conclusion, this study suggests a crosstalk between LepR and ERa, and could envisage novel therapeutic settings aimed at targeting the LepR in breast cancers.

Inhibition of Leptin and Leptin Receptor Gene Expression by Silibinin-Curcumin Combination

“…A study showed that inhibition of leptin receptor by siRNA leads to down-regulation of ERα gene expression (Fusco et al, 2010). Thus, modulation of each involving gene (leptin, leptin receptors, ER) can cause interference in the entire pathway in ER+ cells and based on these mechanisms, the synergistic inhibitory effects of curcumin and silibinin on leptin expression are, therefore, due to their effects on the same targets.…”

Increased peroxisome proliferator-activated receptor γ expression levels in visceral adipose tissue, and serum CCL2 and interleukin-6 levels during visceral adipose tissue accumulation

“…Excessive accumulation of visceral adipose tissues in humans is associated with various chronic diseases, including type II diabetes, high blood pressure, hypertension, dyslipidemia, various types of cancer and cardiovascular diseases (5,6). Evidence has suggested that the excessive accumulation of adipose tissue alters the secretion of adipokines, including leptin, interleukin (IL)-6, resistin, CCL2, adiponectin and tumour necrosis factor (TNF)-α, which promote proliferation, angiogenesis and invasion in certain types of cancer (7).…”

Targeting the leptin receptor: a potential new mode of treatment for breast cancer

“…The hormone can also increase the invasiveness and metastatic potential of BC cells [15], and promote angiogenesis while maintaining a microenvironment favorable for BC development [16]. Furthermore, leptin is known to crosstalk with and transactivate several pathways that are targets for BC therapy, including the estrogen, EGF receptor and HER2 pathways [13,17,18]. Consequently, in recent years the leptin/ObR system has emerged as a new and promising target in BC therapy [13,19].…”