Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

Samady, Laila; Dennis, Jonathan J.; Budhram-Mahadeo, Vishwanie; Latchman, David S.

doi:10.4161/cbt.3.3.698

Cited by 79 publications

(63 citation statements)

References 36 publications

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“…Homeobox genes can also contribute to breast cancer progression by influencing cell cycle regulation, apoptosis, angiogenesis and metastasis (Care et al, 2001;Samady et al, 2004;Satoh et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

BARX2 and estrogen receptor-α (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion

Stevens

Meech

2006

Oncogene

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The estrogen receptor-a gene (ESR1) was previously identified as a direct target of the homeobox transcription factor BARX2 in MCF7 cells. Here, we show that BARX2 and ESR1 proteins bind to different ESR1 gene promoters and regulate the expression of alternatively spliced mRNAs that encode 66 and 46 kDa ESR1 protein isoforms. BARX2 increases the expression of both ESR1 isoforms; however, it has a greater effect on the 46 kDa isoform, leading to an increased ratio between the 46 and 66 kDa proteins. BARX2 also influences estrogen-dependent processes such as anchorage-independent growth and modulates the expression of the estrogen-responsive genes SOX5, RBM15, Dynein and Mortalin. In addition, BARX2 expression promotes cellular invasion and increases the expression of active matrix metalloproteinase-9 (MMP9). BARX2 also increases the expression of the tissue inhibitor of metalloproteinase (TIMP) genes, TIMP1 and TIMP3, in cooperation with estrogen signaling. Overall, these data indicate that BARX2 and ESR1 may coordinately regulate cell growth, survival and invasion pathways that are critical to breast cancer progression.

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Section: Introductionmentioning

confidence: 99%

BARX2 and estrogen receptor-α (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion

Stevens

Meech

2006

Oncogene

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“…To confirm the results obtained by the cancer array previously carried out 20 and to provide insight into the molecular mechanisms involving Brn-3b in tumor progression and invasion, we utilized quantitative real time reverse transcription/polymerase chain reaction (RT-PCR) assays to quantitate and compare the levels of plakoglobin mRNA and the related factor, b-catenin mRNAs in the Brn-3b over-expressing or anti-sense MCF7 cell lines.…”

Section: Brn-3b Expression Inversely Correlates With Plakoglobin Exprmentioning

confidence: 99%

“…This approach uses a fluorescence-based method for detection of amplification product that has been previously described. 20 Standard curves were generated for each gene of interest using 10-fold serial dilutions of a known amount of cDNA from MCF7 cell lines overexpressing Brn-3b. This allows the generation of values corresponding to unknown quantities of mRNA in test samples.…”

Section: Real-time Pcr Assaymentioning

confidence: 99%

“…11 In order to understand the specific role of Brn-3b in breast cancer, we have identified the genes whose expression alters with Brn-3b over-expression by cDNA micro-array analysis, using human breast cancer cells that stably overexpress Brn-3b or cells in which Brn-3b expression has been reduced using an anti-sense approach. 20 We have found that more than 50 cancer-related genes from the cancer array were modulated by Brn-3b. We have specifically shown that Brn-3b is implicated in cell proliferation, by upregulation of genes involved in cell cycle regulation such as cyclin-dependent kinase 4, CDK4 and that Brn-3b can activate the CDK4 promoter.…”

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confidence: 99%

“…We have specifically shown that Brn-3b is implicated in cell proliferation, by upregulation of genes involved in cell cycle regulation such as cyclin-dependent kinase 4, CDK4 and that Brn-3b can activate the CDK4 promoter. 20 Previous initial studies using the cancer array also suggested that plakoglobin (g-catenin) mRNA levels might be regulated by Brn-3b. Here, we have shown that high levels of Brn-3b mRNA and protein were accompanied by low levels of plakoglobin mRNA and protein in breast cancer cell lines manipulated to express different levels of Brn-3b.…”

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confidence: 99%

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

Samady

Faulkes

Budhram-Mahadeo

et al. 2005

Intl Journal of Cancer

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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 ...

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Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin‐induced skin fibrosis

Huber¹,

Distler

Moritz

et al. 2007

Arthritis & Rheumatism

147

124

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Objective. Tissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokinedriven fibrotic responses in vitro and in vivo.Methods. Skin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Col␣1(I) and fibronectin were measured using real-time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobilty shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin-induced fibrosis.Results. Reductions in the cytokine-induced transcription of Col␣1(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA-stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up-regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycininduced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo.Conclusion. These findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine-driven induction of matrix synthesis that leads to fibrosis.

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Activation of CDK4 Gene Expression in Human Breast Cancer Cells by the Brn-3b POU Family Transcription Factor

Cited by 79 publications

References 36 publications

BARX2 and estrogen receptor-α (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion

BARX2 and estrogen receptor-α (ESR1) coordinately regulate the production of alternatively spliced ESR1 isoforms and control breast cancer cell growth and invasion

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

Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin‐induced skin fibrosis

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