title: Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression.
abstract: Leptin, a cytokine mainly produced by adipocytes, seems to play a crucial role in mammary carcinogenesis. In the present study, we explored the mechanism of leptin-mediated promotion of breast tumor growth using xenograft MCF-7 in 45-day-old female nude mice, and an in vitro model represented by MCF-7 three-dimensional cultures. Xenograft tumors, obtained only in animals with estradiol (E(2)) pellet implants, doubled control value after 13 weeks of leptin exposure. In three-dimensional cultures, leptin and/or E(2) enhanced cell-cell adhesion. This increased aggregation seems to be dependent on E-cadherin because it was completely abrogated in the presence of function-blocking E-cadherin antibody or EGTA, a calcium-chelating agent. In three-dimensional cultures, leptin and/or E(2) treatment significantly increased cell growth, which was abrogated when E-cadherin function was blocked. These findings well correlated with an increase of mRNA and protein content of E-cadherin in three-dimensional cultures and in xenografts. In MCF-7 cells both hormones were able to activate E-cadherin promoter. Mutagenesis studies, electrophoretic mobility shift assay, and chromatin immunoprecipitation assays revealed that cyclic AMP-responsive element binding protein and Sp1 motifs, present on E-cadherin promoter, were important for the up-regulatory effects induced by both hormones on E-cadherin expression in breast cancer MCF-7 cells. In conclusion, the present study shows how leptin is able to promote tumor cell proliferation and homotypic tumor cell adhesion via an increase of E-cadherin expression. This combined effect may give reasonable emphasis to the important role of this cytokine in stimulating primary breast tumor cell growth and progression, particularly in obese women.
authors.affiliation: Department of Cellular Biology and Pharmaco-Biology, University of Calabria, Rende, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Mauro
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Bossi
authors.forename: Michele
authors.initials: M
authors.lastname: Pellegrino
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Sara
authors.initials: S
authors.lastname: Morales
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Viviana
authors.initials: V
authors.lastname: Bartella
authors.forename: Ivan
authors.initials: I
authors.lastname: Casaburi
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D018450:Disease Progression; D004533:Egtazic Acid / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C115163:CREB1 protein, human; D015820:Cadherins; D017362:Cyclic AMP Response Element-Binding Protein; D004273:DNA, Neoplasm; D047628:Estrogen Receptor alpha; D020738:Leptin; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; D004958:Estradiol; D004533:Egtazic Acid