期刊
MOLECULAR CANCER RESEARCH
卷 14, 期 5, 页码 470-481出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-15-0423
关键词
-
资金
- American Italian Cancer Foundation
- Susan G. Komen for the cure grants
- Promise grant [PG12221410]
- Stand Up 2 Cancer Dream Team Translational Research Grant [SU2C-AACR-DT0409]
- NIH [P50 CA058183, CA186784-01]
- Cancer Center Grant [P30CA125123]
- EIF/Lee Jeans Breast Cancer Research Program
- Breast Cancer Research Foundation
- Cancer Prevention Research Institute of Texas [CPRIT RP140102]
- Baylor College of Medicine Comprehensive Cancer Training Program
The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo. AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. Implications: AP-1 represents a viable therapeutic target to overcome endocrine resistance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据