Abstract
Abstract Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and resistance to anticancer therapies. These cells rely for their properties on complex interactions with the tumor microenvironment through networks of cytokines and growth factors. In this study, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using breast cancer cell lines and patient-derived samples. We found that conditioned media (CM) from cancer associated fibroblasts and breast adipocytes significantly increase mammosphere formation in breast cancer cells. Depletion of leptin from stromal cell-CM as well as inhibition of leptin signaling by using a full leptin receptor antagonist peptide LDFI completely abrogated this effect. Accordingly, mammosphere cultures exhibited increased leptin receptor expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology in mammosphere cells treated with stromal cell-CM and leptin. Interestingly, leptin is able to increase the mammosphere formation in metastatic breast cancer cells isolated from patients (n = 10) and this can be blocked by using peptide LDFI. In addition, leptin receptor (OBR) mRNA expression, analyzed in cells from metastatic fluids, directly correlated with mammosphere formation activity ex vivo (r=0.68, p= 0.05; n = 8). Finally, Kaplan–Meier survival curves indicated that OBR expression correlated with reduced overall survival in breast carcinomas (HR=1.9, p=0.022). Together, our results suggest that leptin/leptin receptor may represent a potential therapeutic target that can block the stromal-tumor interactions that drive BCSC-mediated disease progression. Citation Format: Giordano C, Panza S, Chemi F, Barone I, Bonofiglio D, Cordella A, Hashim A, Györffy B, Simões BM, Clarke RB, Weisz A, Catalano S, Andò S. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-06.
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