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.