title: Leptin increases HER2 protein levels through a STAT3-mediated up-regulation of Hsp90 in breast cancer cells.
abstract: Obesity condition confers risks to breast cancer development and progression, and several reports indicate that the adipokine leptin, whose synthesis and plasma levels increase with obesity, might play an important role in modulating breast cancer cell phenotype. Functional crosstalk occurring between leptin and different signaling molecules contribute to breast carcinogenesis. In this study, we show, in different human breast cancer cell lines, that leptin enhanced the expression of a chaperone protein Hsp90 resulting in increased HER2 protein levels. Silencing of Hsp90 gene expression by RNA interference abrogated leptin-mediated HER2 up-regulation. Leptin effects were dependent on JAK2/STAT3 activation, since inhibition of this signaling cascade by AG490 or ectopic expression of a STAT3 dominant negative abrogated leptin-induced HER2 and Hsp90 expressions. Functional experiments showed that leptin treatment significantly up-regulated human Hsp90 promoter activity. This occurred through an enhanced STAT3 transcription factor binding to its specific responsive element located in the Hsp90 promoter region as revealed by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. Analysis of HER2, Akt and MAPK phosphorylation levels revealed that leptin treatment amplified the responsiveness of breast cancer cells to growth factor stimulation. Furthermore, we found that long-term leptin exposure reduced sensitivity of breast cancer cells to the antiestrogen tamoxifen. In the same experimental conditions, the combined treatment of tamoxifen with the Hsp90 inhibitor 17-AAG completely abrogated leptin-induced anchorage-independent breast cancer cell growth. In conclusion, our results highlight, for the first time, the ability of the adipocyte-secreted factor leptin to modulate Hsp90/HER2 expressions in breast cancer cells providing novel insights into the molecular mechanism linking obesity to breast cancer growth and progression.
authors.affiliation: Centro Sanitario, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.forename: Donatella
authors.initials: D
authors.lastname: Vizza
authors.forename: Salvatore
authors.initials: S
authors.lastname: Panza
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Daniela
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: Marilena
authors.initials: M
authors.lastname: Lanzino
authors.forename: Diego
authors.initials: D
authors.lastname: Sisci
authors.forename: Francesca
authors.initials: F
authors.lastname: De Amicis
authors.forename: Suzanne A W
authors.initials: SA
authors.lastname: Fuqua
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D020738:Leptin / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018841:HSP90 Heat-Shock Proteins; D020738:Leptin; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D013629:Tamoxifen