Open AccessThe HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway
Author(s) -
Kideok Jin,
Xiangjun Kong,
Tariq Shah,
MarieFrance Penet,
Flonné Wildes,
Dennis Sgroi,
XiaoJun Ma,
Yi Huang,
Anne Kallioniemi,
Göran Landberg,
Ivan Bièche,
Xinyan Wu,
Peter E. Lobie,
Nancy E. Davidson,
Zaver M. Bhujwalla,
Tao Zhu,
Saraswati Sukumar
Publication year - 2011
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1018859108
Subject(s) - tamoxifen , estrogen receptor , cancer research , breast cancer , biology , cancer , regulator , receptor tyrosine kinase , signal transduction , gene , microbiology and biotechnology , genetics
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.