The Brn‐3b POU family transcription factor represses plakoglobin gene expression in human breast cancer cells

Abstract

The Brn-3b transcription factor has been shown to be overexpressed in human breast cancer cells and contributes toward cell growth regulation. Using micro-arrays, more than 50 cancerrelated genes regulated by Brn-3b in human breast cancer cells have been identified. For example, Brn-3b activates the cell cycle regulator CDK4 that provides a mechanism by which Brn-3b controls the growth of breast cancer cells. Here, we show that Brn-3b regulates plakoglobin (c-catenin), a member of the catenin family involved in cell-cell adhesion and signal transduction. Brn-3b expression inversely correlates with plakoglobin expression at both mRNA and protein levels in breast cancer cell lines and human breast biopsies. In contrast, no significant correlation was observed between Brn-3b expression and b-catenin, or between Brn-3b expression and E-cadherin expression. Brn-3b represses the plakoglobin promoter via a Brn-3 consensus binding site contained within the region 2965 to 2593 relative to the transcriptional start site. Both repression of the promoter and binding of Brn-3b are lost when this site is mutated. To our knowledge, this is the first time that a Brn-3b POU family transcription factor has been shown to regulate a member of the catenin family, which provides insight into the molecular mechanisms by which Brn-3b expression may favour breast cancer progression and tumor invasion. ' 2005 Wiley-Liss, Inc.Key words: breast cancer; metastasis; Brn-3b transcription factor; Plakoglobin (g-catenin), micro-arrayThe POU (Pit-Oct-Unc) family of transcription factors were originally identified on the basis of a common DNA binding domain, referred to as the POU domain, present in the mammalian transcription factors Pit-1, Oct-1 and Oct-2 and the nematode regulatory protein Unc-86. 1,2 A number of POU family transcription factors have been identified in the nervous system where they have been shown to play a critical role in the regulation of gene expression. Thus, the closely related POU family transcription factors Brn-3a, Brn-3b and Brn-3c were originally identified on the basis of their distinct but overlapping patterns of gene expression in the developing and adult nervous systems. [3][4][5][6] Inactivation of the individual genes encoding these factors has been shown to produce defects in the development of specific parts of the nervous system. 7-9 However, expression of Brn-3a and Brn-3b has also been observed in non-neuronal cells such as in the testis, 10 breast 11 and cervix. 4,12 Changes in expression of Brn-3a and Brn-3b have been reported in tumors derived from the cells which normally express them, suggesting a role for this family of transcription factors in cancer. Indeed, Brn-3a has been shown to be overexpressed in aggressive neuroendocrine tumors, 13 whilst Brn-3b is expressed at high levels in human neuroblastomas. 14,15 Similarly, Brn-3a is highly overexpressed in human cervical intraepithelial neoplasia grade 3 (CIN3), compared to normal human cervical samples. 12 Interestingly, our previous studies have ...

Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERα and growth factors via MAPK pathway

“…For example, Brn-3b might contribute to cellular proliferation by transactivating the promoters of cell cycle regulators, CDK4 [4] and cyclin D1 [5] whilst repressing the tumour suppressor, BRCA1 [6]. However, its effects on drug resistance and migration are likely to be associated with the ability of Brn-3b to regulate other genes, for example, to transactivate Hsp27 [7] whilst repressing adhesion molecules, for example, γ-catenin [8]. …”

“…For example, increased proliferation by Brn-3b may be associated with its ability to transactivate the promoters of genes required for cell cycle progression such as cyclin-dependent kinase 4 ( CDK4 ) [4] and its regulatory partner cyclin D1 [5], which are required, whilst repressing breast cancer susceptibility gene 1 ( BRCA1 ) [6], which is associated with cell cycle arrest in breast cancer cells. Invasiveness and drug resistance associated with Brn-3b in cancer cells are linked with its ability to transactivate genes such as the small heat shock protein 27 ( HSP27 ) [7] whilst repressing promoters of genes encoding adhesion molecules, for example, γ-catenin/plakoglobin [8]. …”

Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression

“…When elevated in these tumours, Brn-3b transcription factor can alter the growth and behavior of cells by modulating expression of target genes that help to confer growth advantages to the cells, e.g. increasing CDK4 (associated cell cycle progression) and HSP27 (involved in migration and drug resistance) but represses the tumour suppressor protein, BRCA1 (7,8,18,23,57). However, its ability to alter p53 mediated effects becomes quite important in these cell types.…”

Tip60 Protein Isoforms and Altered Function in Skin and Tumors that Overexpress Ornithine Decarboxylase

“…In that context, it is intriguing that our transcription factor screen also identified the POU transcription factor Brn-3 as a factor whose interaction with Tip60 is negatively affected in K6/ODC skin and to an even greater extent in ODC/Ras tumors. The Brn-3 family of transcription factors positively and negatively regulates many genes, including some critical for the somatosensory, visual, and auditory/vestibular systems (42), as well as genes relevant to cancer (43). Because the different Brn-3 family members can exert opposite and antagonistic effects on target 1 L. Lan, B. Paul, and S. Gilmour.…”