title: Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.
abstract: 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.
authors.affiliation: Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chemi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panza
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.affiliation: IRCCS SDN (Istituto di Ricerca Diagnostica e Nucleare), Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Cordella
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Campana
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.|Norwegian Centre for Molecular Medicine (NCMM), University of Oslo, Oslo, Norway.
authors.forename: Adnan
authors.initials: A
authors.lastname: Hashim
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Rizza
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Leggio
authors.affiliation: MTA TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.|2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.|MTA-SE Pediatrics and Nephrology Research Group, Budapest, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Győrffy
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University Manchester, Manchester, UK.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Simões
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University Manchester, Manchester, UK.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.affiliation: Laboratory of Molecular Medicine and Genomics, Department of Medicine and Surgery, University of Salerno, Baronissi, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Weisz
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy.|Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D020738:Leptin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D017077:Culture Media, Conditioned; D018841:HSP90 Heat-Shock Proteins; D020738:Leptin; D054411:Receptors, Leptin
keywords: CAFs; breast cancer; breast cancer stem cells; leptin; microenvironment