Cofactor of BRCA1

A novel transcription factor regulator in upper gastrointestinal adenocarcinomas

Patricia A. McChesney, Sarah E. Aiyar, Ok Jae Lee, Alexander Zaika, Christopher Moskaluk, Rong Li, Wael El-Rifai

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Cofactor of BRCA1 (COBRA1) is a newly characterized member of the negative elongation factor (NELF) complex. In this work, we show that COBRA1 is overexpressed in the majority of primary upper gastrointestinal adenocarcinomas (UGC), and its overexpression correlates with down-regulation of TFF1. We have detected overexpression of COBRA1 mRNA using quantitative real-time reverse transcription-PCR in 28 (79%) primary UGCs. Immunohistochemical analysis of UGC tissue arrays that contained 70 tumor samples showed moderate-strong staining for COBRA1 in 60 (84%) tumors. Interestingly, the tumor samples showed absent-weak staining for TFF1 in 45 (65%) of the tumors. Simultaneous loss of TFF1 expression and overexpression of COBRA1 was observed in 42 of 70 (60%) tumors. Using small interfering RNA technology with gastric cancer cells, we have shown that COBRA1 inhibition leads to increased TFF1 promoter activity and gene expression. Promoter analysis of TFF1 indicated that regulation of TFF1 by COBRA1 is estrogen independent in contrast to breast cancer. Moreover, COBRA1 regulation of TFF1 in gastric cancer cells was independent of NELF-E. Using several truncated mutants and site mutants of the TFF1 promoter, we have shown that COBRA1 can negatively regulate the activator protein-1 (AP-1) complex at the TFF1 promoter and thus down-regulate TFF1 expression in gastric cancer cell lines. Electrophoretic mobility shift assay showed that COBRA1 attenuates AP-1 binding to DNA. Our results suggest COBRA1 as a novel oncogene in UGCs that regulate AP-1 binding and the expression of TFF1 in upper gastric epithelia.

Original languageEnglish (US)
Pages (from-to)1346-1353
Number of pages8
JournalCancer Research
Volume66
Issue number3
DOIs
StatePublished - Feb 1 2006
Externally publishedYes

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Adenocarcinoma
Transcription Factors
Transcription Factor AP-1
Stomach Neoplasms
Neoplasms
Protein Binding
Down-Regulation
Staining and Labeling
Electrophoretic Mobility Shift Assay
Oncogenes
Small Interfering RNA
Reverse Transcription
Stomach
Estrogens
Epithelium
Breast Neoplasms
Technology
Gene Expression
Cell Line
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cofactor of BRCA1 : A novel transcription factor regulator in upper gastrointestinal adenocarcinomas. / McChesney, Patricia A.; Aiyar, Sarah E.; Lee, Ok Jae; Zaika, Alexander; Moskaluk, Christopher; Li, Rong; El-Rifai, Wael.

In: Cancer Research, Vol. 66, No. 3, 01.02.2006, p. 1346-1353.

Research output: Contribution to journalArticle

McChesney, Patricia A. ; Aiyar, Sarah E. ; Lee, Ok Jae ; Zaika, Alexander ; Moskaluk, Christopher ; Li, Rong ; El-Rifai, Wael. / Cofactor of BRCA1 : A novel transcription factor regulator in upper gastrointestinal adenocarcinomas. In: Cancer Research. 2006 ; Vol. 66, No. 3. pp. 1346-1353.
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