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?-catenin regulates c-Myc and CDKN1A expression in breast cancer cells.

ABSTRACT: We previously reported that the Wnt pathway is preferentially activated in basal-like breast cancer. However, the mechanisms by which the Wnt pathway regulates down-stream targets in basal-like breast cancer, and the biological significance of this regulation, are poorly understood. In this study, we found that c-Myc is highly expressed in the basal-like subtype by microarray analyses and immunohistochemical staining. After silencing ?-catenin using siRNA, c-Myc expression was decreased in non-basal-like breast cancer cells. In contrast, c-Myc mRNA and protein expression were up-regulated in the basal-like breast cancer cell lines. Decreased c-Myc promoter activity was observed after inhibiting ?-catenin by siRNA in non-basal-like breast cancer cells; however, inhibition of ?-catenin or over-expression of dominant-negative LEF1 had no effect on c-Myc promoter activity in basal-like breast cancer cell lines. In addition, CDKN1A mRNA and p21 protein expression were significantly increased in all breast cancer cell lines upon ?-catenin silencing. Interestingly, inhibiting ?-catenin expression alone did not induce apoptosis in breast cancer cell lines despite c-Myc regulation, but we observed a modest increase of cells in the G1 phase of the cell cycle and decrease of cells in S phase upon ?-catenin silencing. Our findings suggest that the regulation of c-Myc in breast cancer cells is dependent on the molecular subtype, and that ?-catenin-mediated regulation of c-Myc and p21 may control the balance of cell death and proliferation in breast cancer.

SUBMITTER: Xu J

PROVIDER: S-EPMC4529819 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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β-catenin regulates c-Myc and CDKN1A expression in breast cancer cells.

Xu Jinhua J Chen Yinghua Y Huo Dezheng D Khramtsov Andrey A Khramtsova Galina G Zhang Chunling C Goss Kathleen H KH Olopade Olufunmilayo I OI

Molecular carcinogenesis 20150208 5

We previously reported that the Wnt pathway is preferentially activated in basal-like breast cancer. However, the mechanisms by which the Wnt pathway regulates down-stream targets in basal-like breast cancer, and the biological significance of this regulation, are poorly understood. In this study, we found that c-Myc is highly expressed in the basal-like subtype by microarray analyses and immunohistochemical staining. After silencing β-catenin using siRNA, c-Myc expression was decreased in non-b ...[more]

PMID: 25663530

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Project description:BackgroundThe BRCA1 gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate BRCA1 expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that BRCA1 is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of BRCA1 by c-Myc.Methodsc-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells. BRCA1 mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and BRCA1 promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the BRCA1 promoter region. The association of c-Myc with the BRCA1 promoter in vivo was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the BRCA1 promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay.ResultsDepletion of c-Myc was found to be correlated with reduced expression levels of BRCA1 mRNA and BRCA1 protein. Depletion of c-Myc decreased BRCA1 promoter activity, while ectopically expressed c-Myc increased BRCA1 promoter activity. In the distal BRCA1 promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions in vivo. Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc-dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity.ConclusionsThe distal BRCA1 promoter region is associated with c-Myc and contributes to BRCA1 gene activation.

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?-catenin regulates c-Myc and CDKN1A expression in breast cancer cells.

Publications

β-catenin regulates c-Myc and CDKN1A expression in breast cancer cells.

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