Evidences that leptin up-regulates E-cadherin expression in breast cancer: effects on tumor growth and progression.
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.
Mauro
Loredana
L
Department of Cellular Biology and Pharmaco-Biology, University of Calabria, Rende, Italy.
Catalano
Stefania
S
Bossi
Gianluca
G
Pellegrino
Michele
M
Barone
Ines
I
Morales
Sara
S
Giordano
Cinzia
C
Bartella
Viviana
V
Casaburi
Ivan
I
Andò
Sebastiano
S
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
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