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

Kideok Jin, Xiangjun Kong, Tariq Shah, Marie France Penet, Flonne Wildes, Dennis C. Sgroi, Xiao Jun Ma, Yi Huang, Anne Kallioniemi, Goran Landberg, Ivan Bieche, Xinyan Wu, Peter E. Lobie, Nancy E. Davidson, Zaver M. Bhujwalla, Tao Zhu, Saraswati Sukumar

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64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2736-2741
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number8
DOIs
StatePublished - Feb 21 2012

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    Jin, K., Kong, X., Shah, T., Penet, M. F., Wildes, F., Sgroi, D. C., Ma, X. J., Huang, Y., Kallioniemi, A., Landberg, G., Bieche, I., Wu, X., Lobie, P. E., Davidson, N. E., Bhujwalla, Z. M., Zhu, T., & Sukumar, S. (2012). The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway. Proceedings of the National Academy of Sciences of the United States of America, 109(8), 2736-2741. https://doi.org/10.1073/pnas.1018859108