title: Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy.
abstract: Cancer-associated fibroblasts (CAFs), the principal components of the tumor stroma, play a central role in cancer development and progression. As an important regulator of the crosstalk between breast cancer cells and CAFs, the cytokine leptin has been associated to breast carcinogenesis. The nuclear Farnesoid X Receptor-(FXR) seems to exert an oncosuppressive role in different tumors, including breast cancer. Herein, we demonstrated, for the first time, that the synthetic FXR agonist GW4064, inhibiting leptin signaling, affects the tumor-promoting activities of CAFs in breast malignancy. GW4064 inhibited growth, motility and invasiveness induced by leptin as well as by CAF-conditioned media in different breast cancer cell lines. These effects rely on the ability of activated FXR to increase the expression of the suppressor of the cytokine signaling 3 (SOCS3) leading to inhibition of leptin-activated signaling and downregulation of leptin-target genes. In vivo xenograft studies, using MCF-7 cells alone or co-injected with CAFs, showed that GW4064 administration markedly reduced tumor growth. Interestingly, GW4064-treated tumors exhibited decreased levels of leptin-regulated proteins along with a strong staining intensity for SOCS3. Thus, FXR ligands might represent an emerging potential anti-cancer therapy able to block the tumor supportive role of activated fibroblasts within the breast microenvironment.
authors.affiliation: Centro Sanitario, University of Calabria, Arcavacata di Rende, CS, 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, CS, 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, CS, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vircillo
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, 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, CS, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Malivindi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Gelsomino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Pellegrino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Rago
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Mauro
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Panno
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, 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, CS, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Centro Sanitario, University of Calabria, Arcavacata di Rende, CS, Italy.|Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, CS, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D008819:Mice, Nude; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D007555:Isoxazoles; D020738:Leptin; D018160:Receptors, Cytoplasmic and Nuclear; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000099150:Receptor, Farnesoid X-Activated; C106644:SOCS3 protein, human; C412815:GW 4064