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Leptin Increases HER2 Stability through HSP90 in Breast Cancer Cells
Author(s) -
Giordano Cinzia,
Vizza Donatella,
Rovito Daniela,
Barone Ines,
Bonofiglio Daniela,
Panza Salvatore,
Lanzino Marilena,
Fuqua Suzanne,
Catalano Stefania,
Andò Sebastiano
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.834.3
Subject(s) - leptin , breast cancer , endocrinology , medicine , leptin receptor , tamoxifen , trastuzumab , stat3 , protein kinase b , cancer research , cancer , biology , phosphorylation , obesity , microbiology and biotechnology
High serum levels of the adipocyte‐derived hormone leptin in obesity are a risk for breast cancer in postmenopausal women. The HER2/Neu receptor, overexpressed in 25% of human breast cancers, has been associated with endocrine resistance. Here, we evaluated the link between leptin and HER2 in human MCF‐7 breast cancer cells and in MCF‐7/HER2‐18 cells stably overexpressing HER2. We found that leptin treatment increased HER2 protein levels, without affecting HER2 mRNA levels. Leptin enhanced the expression of HSP90, a chaperone protein that regulates HER2 degradation, and increased HER2/HSP90 interaction. These events were dependent on JAK2/STAT3 activation, since inhibition of this cascade by AG490 or a STAT3 dominant negative abrogated leptin‐induced HER2 expression. Moreover, leptin treatment increased EGF‐mediated HER2, AKT and MAPK phosphorylation. Anchorage‐independent growth assays revealed that long term leptin treatment reduced sensitivity to the antiestrogen tamoxifen, while increased responsiveness to herceptin, a monoclonal antibody against HER2. We demonstrate that leptin, through HSP90, enhances HER2 stability, providing further insights into the crucial role of leptin in modulating tumor growth and aggressiveness. Clinically, our results suggest that leptin and HSP90 might be novel targets for therapeutic intervention in breast cancer, especially in obese patients.