Leptin receptor maintains cancer stem-like properties in triple negative breast cancer cells

Abstract

Despite new therapies, breast cancer continues to be the second leading cause of cancer mortality in women a consequence of recurrence and metastasis. In recent years, a population of cancer cells has been identified, called cancer stem cells (CSCs) with self-renewal capacity, proposed to underlie tumor recurrence and metastasis. We previously showed that the adipose tissue cytokine LEPTIN, increased in obesity, promotes the survival of CSCs in vivo. Here, we tested the hypothesis that the Leptin Receptor (LEPR), expressed in mammary cancer cells, is necessary for maintaining CSC-like and metastatic properties. We silenced LEPR via shRNA lentivirus transduction and determined that expression of stem cell self-renewal transcription factors NANOG, SOX2, and OCT4 are inhibited. LEPR-NANOG signaling pathway is conserved between species because we can rescue NANOG expression in human LEPR-silenced cells with the mouse LepR. Using a NANOG promoter GFP reporter, we showed that LEPR is enriched in NANOG promoter active (GFP+) cells. Using lineage tracing, we showed that the GFP+ cells exhibit symmetric and asymmetric division and cell death. LEPR silenced MDA-MB-231 cells exhibit a mesenchymal to epithelial transition morphologically, increased E-CADHERIN and decreased VIMENTIN expression compared to control cells. Finally, LEPR silenced cells exhibit reduced cell proliferation, self-renewal in tumorsphere assays, and tumor outgrowth in xenotransplant studies. Given the emergence of NANOG as a pro-carcinogenic protein in multiple cancers, these studies suggest that inhibition of LEPR may be a promising therapeutic approach to inhibit NANOG and thereby neutralize CSC functions.

Energy homeostasis genes and survival after breast cancer diagnosis: the Breast Cancer Health Disparities Study

“…LEPR is a cytokine receptor that is highly expressed in multiple tumors, including breast cancer, and in breast cancer LEPR expression is directly correlated with poor prognosis (37). LEP is predominately secreted by adipose tissue, and functions as an anorexigenic hormone responsible for appetite suppression and maintenance of EH.…”

Emerging Concepts Linking Obesity with the Hallmarks of Cancer

“…Serum from obese patients increased a breast cancer stem cell population by 30% compared with 7% for lean control serum [103]. In breast cancer cell lines, silencing the leptin receptor may reduce cancer stem cell-like properties and EMT transition [104], and treatment of breast cancer cells with leptin from tumour stroma induced stem-like properties [105]. In cell line models of breast cancer, leptin appeared to activate the proinflammatory STAT3 pathway, recruiting G9a and causing repression of miR-200c via epigenetic silencing to induce the EMT stem cell phenotype [106].…”

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

“…Also, TISCs demonstrate increased phosphorylation of pluripotency-associated oncogene Stat3 and induction of OCT4 and SOX2 in response to leptin [122]. It is suggested that leptin receptor plays an important role in the expression of Nanog, OCT4 and SOX2 in BCSCs, viability of BCSCs, proliferation and tumor-initiating activity [123]. These findings raise the possibility that obesity and its associated increased level of leptin-network can act as a mechanistic link between obesity, increased maintenance of cancer stem cells, augmented cancer recurrence, increased distant metastasis and overall poor survival.…”