Leptin as a Mediator of Tumor‐Stromal Interactions Promotes Breast Cancer Stem Cell Activity.

Abstract

Breast cancer stem‐like cells (BCSC) are responsible for tumor initiation, maintenance, and metastases. BCSC rely for their properties on complex interactions with the tumor microenvironment through networks of cytokines and growth factors. Leptin, a well‐known cytokine involved in breast cancer progression, plays a crucial role in the tumor‐stromal crosstalk. Thus, we investigated how tumor microenvironmental factors and especially leptin may affect BCSC activity using MCF‐7 breast cancer cells and patient‐derived samples.Treatment of mammosphere cultures with conditioned media (CM) from cancer associated fibroblasts and breast adipocytes resulted in a significant increase in mammosphere‐forming efficiency (MFE). Depletion of leptin from stromal cell‐CM completely abrogated this effect. Accordingly, mammosphere cultures exhibited increased leptin receptor expression and leptin exposure enhanced MFE. Microarray analyses revealed a similar expression profile of genes involved in stemness and cell proliferation in mammospheres treated with stromal cell‐CM and leptin. Finally, leptin significantly increased MFE in patient‐derived samples (metastatic ascites and pleural effusion fluid) and leptin mRNA levels in peritumoral adipose tissue of breast cancer patients were positively correlated with MFE (r= 0.449; P 蠄 0.05).Our study highlights leptin as an important paracrine molecule that mediates the microenvironment effects on BCSC activity.