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Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2736-41. doi: 10.1073/pnas.1018859108. Epub 2011 Jun 20.

The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway.

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  • 1Breast Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.

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.

PMID:
21690342
[PubMed - indexed for MEDLINE]
PMCID:
PMC3286915
Free PMC Article

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