Research Papers:

Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity

Cinzia Giordano, Francesca Chemi, Salvatore Panza, Ines Barone, Daniela Bonofiglio, Marilena Lanzino, Angela Cordella, Antonella Campana, Adnan Hashim, Pietro Rizza, Antonella Leggio, Balázs Győrffy, Bruno M. Simões, Robert B. Clarke, Alessandro Weisz, Stefania Catalano and Sebastiano Andò _

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Oncotarget. 2016; 7:1262-1275. https://doi.org/10.18632/oncotarget.6014

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Cinzia Giordano1,*, Francesca Chemi2,*, Salvatore Panza2,*, Ines Barone2, Daniela Bonofiglio2, Marilena Lanzino2, Angela Cordella3, Antonella Campana2, Adnan Hashim4,5, Pietro Rizza2, Antonella Leggio2, Balázs Győrffy7,8,9, Bruno M. Simões6, Robert B. Clarke6, Alessandro Weisz4, Stefania Catalano2,**, Sebastiano Andò1,2,**

1Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy

2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy

3IRCCS SDN (Istituto di Ricerca Diagnostica e Nucleare), Napoli, Italy

4Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy

5Norwegian Centre for Molecular Medicine (NCMM), University of Oslo, Oslo, Norway

6Breast Cancer Now Research Unit, Institute of Cancer Sciences, University Manchester, Manchester, UK

7MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary

82nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary

9MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary

*These authors have equally contributed to this work

**Joint senior authors

Correspondence to:

Sebastiano Andò, e-mail: [email protected]

Stefania Catalano, e-mail: [email protected]

Keywords: breast cancer, leptin, microenvironment, CAFs, breast cancer stem cells

Received: July 08, 2015     Accepted: October 06, 2015     Published: October 27, 2015


Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan–Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression.

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