期刊
ONCOGENE
卷 28, 期 11, 页码 1421-1431出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.485
关键词
YB-1; MET receptor; ChIP-on-chip; basal-like breast cancer; mammary progenitors
资金
- Canadian Breast Cancer Research Alliance
- National Institute of Health
- Michael Smith Foundation
- Canadian Institute for Health
- Canadian Breast Cancer Foundation
- US Department of Defense Breast Cancer Research
- Terry Fox Foundation
- National Cancer Institute of Canada
- Canadian Imperial Bank of Commerce
- Canadian Stem Cell Network Studentship
Basal-like breast cancers (BLBCs) are aggressive tumors with high relapse rates and poor survival. We recently reported that > 70% of primary BLBCs express the oncogenic transcription/translation factor Y-box binding protein-1 (YB-1) and silencing it with small interfering RNAs (siRNAs) attenuates the growth of BLBC cell lines. To understand the basis of these earlier findings, we profiled YB-1: DNA complexes by chromatin immunoprecipitation (ChIP)-on-chip. Several tumor growth-promoting genes such as MET, CD44, CD49f, WNT and NOTCH family members were identified. In addition, YB-1 and MET are coordinately expressed in BLBC cell lines, as well as in normal human mammary progenitor cells. MET was confirmed to be a YB-1 target through traditional ChIP and gel-shift assays. More specifically, YB-1 binds to -1018 bp on the MET promoter. Silencing YB-1 with siRNA decreased MET promoter activity, transcripts, as well as protein levels and signaling. Conversely, expressing wild-type YB-1 or a constitutively active mutant YB-1 (D102) increased MET expression. Finally, silencing YB-1 or MET attenuated anchorage-independent growth of BLBC cell lines. Together, these findings implicate MET as a target of YB-1 that work in concert to promote BLBC growth.
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