Unknown,Transcriptomics,Genomics,Proteomics

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Transcription factor activator protein 2C (TFAP2C) regulates luminal differentiation in mammary development and carcinogenesis

ABSTRACT: Molecular subtypes of breast cancer are characterized by patterns of gene expression, which can be used to predict response to therapy and overall clinical outcome. The luminal breast cancer subtypes are defined by the expression of ER-alpha (ERa) and a set of ERa-associated genes. The transcription factor activator protein 2C (TFAP2C, AP-2C, AP-2g) transcription factor plays a critical role in regulating cell growth and differentiation during ectodermal development and has been implicated in the regulation of ERa and other luminal-associated genes in breast cancer. While TFAP2C has been established as a prognostic factor in human breast cancer, the role of TFAP2C in development of the luminal epithelial cells in the normal mammary gland and in breast cancer have remained elusive. Herein, we demonstrate a critical role of TFAP2C in maintaining the luminal differentiation phenotype during normal mammary development and in luminal breast carcinoma cell lines. Total RNA from MCF7 cells with and without knockdown of TFAP2c. 3 biological replicates, with 2 technical replicates each, were performed for each sample type.

ORGANISM(S): Homo sapiens

SUBMITTER: Thomas Bair

PROVIDER: E-GEOD-44203 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The complexity of gene regulation has created obstacles to defining mechanisms that establish the patterns of gene expression characteristic of the different clinical phenotypes of breast cancer. Transcription factor TFAP2C plays a critical role in the regulation of both estrogen receptor-alpha (ERM-NM-1) and c-ErbB2/HER2 (Her2). Herein, we performed chromatin immunoprecipitation and direct sequencing (ChIP-seq) for TFAP2C in four breast cancer cell lines representing different clinical phenotypes. Comparing the genomic binding sites for TFAP2C in the various cell lines, we identified that glutathione peroxidase (GPX1) is regulated by TFAP2C through an AP-2 regulatory region in the promoter of the GPX1 gene. Knock-down of TFAP2C, but not the related factor TFAP2A, resulted in an abrogation of GPX1 expression. Selenium-dependent GPX activity correlated with endogenous GPX1 expression, and overexpression of exogenous GPX1 induced GPX activity and significantly increased resistance to tert-butyl hydroperoxide. Methylation of the CpG island encompassing the AP-2 regulatory region was identified in cell lines where TFAP2C failed to bind the GPX1 promoter and GPX1 expression was unresponsive to TFAP2C. Furthermore, in cell lines where GPX1 promoter methylation was associated with gene silencing, treatment with 5-aza-dC (an inhibitor of DNA methylation) resulted in activation of GPX1 RNA and protein expression. Methylation of the GPX1 promoter was identified in approximately 20% of primary breast cancers and a highly significant correlation between TFAP2C and GPX1 expression was confirmed when considering only those tumors with an unmethylated promoter, whereas the related factor, TFAP2A, failed to demonstrate a correlation. The results demonstrate that TFAP2C regulates the expression of GPX1, which influences the redox state and sensitivity to oxidative stress induced by peroxides. Given the established role of GPX1 in breast cancer, the results provide an important mechanism for TFAP2C to further influence oncogenesis and progression of breast carcinoma cells. 4 ChIP-Seq data for TFAP2C in human breast carcinoma cell lines MCF-7, BT-474, MDA-MB-453 and SKBR-3.

Project description:Breast Cancer (BC) is one of the main causes of cancer-related death in women. The most widespread BC subtype (75%) is the hormone-dependent, characterized by high expression of Estrogen Receptor Alpha (ERa). ERa exerts its oncogenic activity through the interaction with different co-regulators, carrying out a direct control on gene transcription and thus being the target of specific anticancer therapies. Despite the efficiency of these drugs, 30% of patients develop de novo or acquired resistance mechanisms, caused by alternative mechanisms that bypass antiestrogenic effects determining the onset of relapse. In order to identify new and potentially drugable Era molecular partners, essential genes for BC progression in luminal cell lines assessed by CRISPR-cas assay were compared to ERa interactome, dropping our focus on the tyrosine-protein kinase BAZ1B. BAZ1B is an essential component of the WICH complex and plays a crucial role in chromatin remodelling acting also as transcription regulator. In order to characterize the functional role of BAZ1B in luminal BC, we first employed a TCGA analysis that showed higher expression of BAZ1B in luminal BC associated with a worst overall survival and progression free survival of patient affected by this disease. A transcriptome profiling after BAZ1B silencing was performed in MCF-7 cells, highlighting an impact of modulated genes in key BC pathways including the estrogen signalling. BAZ1B silencing showed also an effect on cell growth, inhibiting cell proliferation and increasing apoptosis activation mechanisms promoted by the loss of ERa protein expression coupled to a reduction of the receptor transactivation activity. Interesting, these effects were confirmed also in antiestrogen (Tamoxifen and Fulvestrant) resistant BC cell models that retain ERa expression, suggesting BAZ1B as a novel and potentially exploitable therapeutic target in the treatment of both hormone dependent and resistant mammary tumours.

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Transcription factor activator protein 2C (TFAP2C) regulates luminal differentiation in mammary development and carcinogenesis

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