The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway.
Jin, K Kong, X Shah, T Penet, M Wildes, F Sgroi, D Ma, X Huang, Y Kallioniemi, A Landberg, Göran
Jin, K
Kong, X
Shah, T
Penet, M
Wildes, F
Sgroi, D
Ma, X
Huang, Y
Kallioniemi, A
Landberg, Göran
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Abstract
Multiple factors including long-term treatment with tamoxifen are involved in the development of selective estrogen receptor (ER) modulator resistance in ERα-positive breast cancer. Many underlying molecular events that confer resistance are known but a unifying theme is yet to be revealed. In this report, we provide evidence that HOXB7 overexpression renders MCF-7 cells resistant to tamoxifen via cross-talk between receptor tyrosine kinases and ERα signaling. HOXB7 is an ERα-responsive gene. Extended treatment of MCF-7 cells with tamoxifen resulted in progressively increasing levels of HOXB7 expression, along with EGFR and EGFR ligands. Up-regulation of EGFR occurs through direct binding of HOXB7 to the EGFR promoter, enhancing transcriptional activity. Finally, higher expression levels of HOXB7 in the tumor significantly correlated with poorer disease-free survival in ERα-positive patients with breast cancer on adjuvant tamoxifen monotherapy. These studies suggest that HOXB7 acts as a key regulator, orchestrating a major group of target molecules in the oncogenic hierarchy. Functional antagonism of HOXB7 could circumvent tamoxifen resistance.
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Date
2012-02-21
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Article
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The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway. 2012, 109 (8):2736-41 Proc Natl Acad Sci USA