Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression

Vernimmen, Douglas; Begon, Dominique; Salvador, Christophe; Gofflot, Stéphanie; Grooteclaes, Madeleine; Winkler, Rosita

doi:10.1042/bj20021238

Cited by 50 publications

(70 citation statements)

References 20 publications

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“…The absence of AP-2 in these cells could explain the result. Indeed, we have shown that AP-2 is responsible for the transcriptional activating properties of this fragment in breast cancer cells (Grooteclaes et al, 1999;Vernimmen et al, 2003). The 6 kb promoter fragment induced a comparable increase in transcriptional activity in both colorectal cell lines.…”

Section: Discussionmentioning

confidence: 92%

“…Indeed, the 500 bp proximal ERBB2 promoter contains two AP-2 binding sites, which contribute to the gene overexpression. The first site is located 215 bp upstream from the transcription initiation site (Bosher et al, 1995), whereas the second lies 501 bp upstream from the transcription start site (Grooteclaes et al, 1999;Vernimmen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear extracts, HTF/AP-2 cis sequence and EMSA were described elsewhere (Schreiber et al, 1989;Vernimmen et al, 2003). Briefly, 2 -4 mg of crude nuclear proteins were incubated with 300 000 c.p.m.…”

Section: Electromobility Shift Assays (Emsa)mentioning

confidence: 99%

“…AP-2 and Ets family transcription factors have been shown to contribute to ERBB2 overexpression in breast cancer cells. The AP-2 transcription factors upregulate the ERBB2 expression by binding to two sites located À213 bp (Bosher et al, 1996) and À500 bp upstream the Cap site (Vernimmen et al, 2003). The Ets transcription factor stimulates ERBB2 expression by preventing the formation of a triplex structure on the core promoter (Scott et al, 2000).…”

mentioning

confidence: 99%

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Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185 c-erbB-2 levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185 c-erbB-2 and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Electromobility Shift Assays (Emsa)mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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“…The anti-actin antibody and the other reagents in the molecular studies were obtained from Sigma Chemical (St. Louis, MO). The plasmids, p756-Luc construct containing 756 bp in the hErbB2-promoter region and the AP-2 binding site mutated p756m-Luc construct were kindly provided by Dr. Winkler R. (University of Liege, Belgium) [15].…”

Section: Methodsmentioning

confidence: 99%

ErbB2 overexpression in p53‐inactivated mammary epithelial cells

2006

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Functional loss of p53 and ErbB2 overexpression are the frequent genetic alterations in human breast carcinomas. Here, we found that ErbB2 expression was upregulated in primary cultured mammary epithelial cells (MECs) isolated from mice with a defect in exons 5 and 6 of the p53 gene (p53 D5,6 ). The reporter gene activity in the p53 D5,6 MECs transfected with the À756 bp flanking region of the hErbB2 gene was higher than the wild type MECs. p53 inactivation selectively increased the level of AP-2a, but not AP-2b and AP-2c and a mutation of the two AP-2 binding sites completely inhibited the reporter activity.

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HER‐2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell‐mediated anti‐tumor immune responses

et al. 2007

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Induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. It is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen-positive clones. To address this question, we used rat neu-overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen-negative variant (ANV). ANV emerged from MMC under pressure from neu-specific T cell responses in vivo. We then cloned residual neu antigen-negative cells from MMC and residual neu antigen-positive cells from ANV. We found marked differences between these neu-negative clones and ANV, demonstrating that the residual neu-negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN-c-secreting T cells, we treated MMC with IFN-c and showed that IFN-c could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neutargeted anti-tumor immune responses.

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Identification of HTF (HER2 transcription factor) as an AP-2 (activator protein-2) transcription factor and contribution of the HTF binding site to ERBB2 gene overexpression

Cited by 50 publications

References 20 publications

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

ErbB2 overexpression in p53‐inactivated mammary epithelial cells

HER‐2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell‐mediated anti‐tumor immune responses

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