Breast Cancer Program, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231-1000, USA.
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2736-41. doi: 10.1073/pnas.1018859108. Epub 2011 Jun 20.
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.
多种因素，包括长期使用他莫昔芬治疗，与 ERα 阳性乳腺癌中选择性雌激素受体 (ER) 调节剂耐药的发展有关。许多赋予耐药性的潜在分子事件是已知的，但尚未揭示统一的主题。在本报告中，我们提供的证据表明，HOXB7 的过表达通过受体酪氨酸激酶和 ERα 信号之间的串扰使 MCF-7 细胞对他莫昔芬产生耐药性。HOXB7 是 ERα 反应性基因。延长 MCF-7 细胞用他莫昔芬治疗会导致 HOXB7 表达水平逐渐增加，同时 EGFR 和 EGFR 配体也增加。EGFR 的上调是通过 HOXB7 与 EGFR 启动子的直接结合发生的，从而增强转录活性。最后，在接受辅助他莫昔芬单药治疗的 ERα 阳性乳腺癌患者中，肿瘤中 HOXB7 的高表达水平与无病生存率降低显著相关。这些研究表明，HOXB7 作为一个关键调节剂，协调致癌级联中的一组主要靶分子。HOXB7 的功能拮抗作用可能会规避他莫昔芬耐药性。
