The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis

Park, J M; Wu, Tong; Cyr, Anthony R.; Woodfield, George W.; Andrade, James P. De; Spanheimer, Philip M.; Li, Tiandao; Sugg, Sonia L.; Lal, Geeta; Domann, Frederick E.; Zhang, W; Weigel, Ronald J.

doi:10.1038/onc.2015.59

Cited by 24 publications

(20 citation statements)

References 40 publications

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“…However, we also identified rare DARs not bound by any reprogramming factors, such as the promoter region of Bex2 (Figures 6E, S6H, and S7C). Motif analysis for this peak suggested a Tfap2c binding site, which was confirmed by published ChIP-seq data (Park et al, 2015). We conclude that regions of hyperaccessibility, revealed only by dissecting the rare intermediates poised to reprogram, identify key cis-regulatory elements critical for reprogramming.…”

Section: Resultssupporting

confidence: 85%

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

et al. 2018

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Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbing additional genes or pathways, during iPSC generation from mouse embryonic fibroblasts. Analysis of these cells uncovered transcription factors (e.g., Tfap2c and Bex2) that are important for reprogramming but dispensable for pluripotency maintenance. Additionally, we observed striking patterns of chromatin hyperaccessibility at pluripotency loci, which preceded gene expression in poised intermediates. Finally, inspection of these hyperaccessible regions revealed an early wave of DNA demethylation that is uncoupled from de novo methylation of somatic regions late in reprogramming. Our study underscores the importance of investigating rare intermediates poised to produce iPSCs, provides insights into reprogramming mechanisms, and offers a valuable resource for the dissection of transcriptional and epigenetic dynamics intrinsic to cell fate change.

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Section: Resultssupporting

confidence: 85%

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

et al. 2018

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“…However, recent studies had revealed dual role of c-Myc in reprogramming, and indicated c-Myc can negatively influences reprogramming by inducing cell apoptosis and creating an epigenetic barrier together with NCoR/SMRT corepressors 52 . In our present study, we found Tfap2c can attenuated the 'side effect' of c-Myc in reprogramming by inhibiting c-Myc-induced apoptosis, in agreement with previous results that Tfap2c decreased apoptosis in an activated Neu model of mammary carcinogenesis 53 . Although the precise mechanism is remained to further investigated, the fact that AP2 transcription factor family function as a negative regulator of c-Myc by impairing DNA binding of c-Myc at specific sites prompts us to speculate Tfap2c may inhibit c-Myc-dependent apoptosis in similar way 54 .…”

Section: Discussionsupporting

confidence: 93%

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition

et al. 2020

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Transcription factors are known to mediate the conversion of somatic cells to induced pluripotent stem cells (iPSCs). Transcription factor TFAP2C plays important roles in the regulation of embryonic development and carcinogenesis; however, the roles of Tfap2c in regulating somatic cell reprogramming are not well understood. Here we demonstrate Tfap2c is induced during the generation of iPSCs from mouse fibroblasts and acts as a facilitator for iPSCs formation. Mechanistically, the c-Myc-dependent apoptosis, which is a roadblock to reprogramming, can be significantly mitigated by Tfap2c overexpression. Meanwhile, Tfap2c can greatly promote mesenchymal-to-epithelial transition (MET) at initiation stage of OSKM-induced reprogramming. Further analysis of gene expression and targets of Tfap2c during reprogramming by RNA-sequencing (RNA-seq) and ChIP-qPCR indicates that TFAP2C can promote epithelial gene expression by binding to their promoters directly. Finally, knockdown of E-cadherin (Cdh1), an important downstream target of TFAP2C and a critical regulator of MET antagonizes Tfap2c-mediated reprogramming. Taken together, we conclude that Tfap2c serves as a strong activator for somatic cell reprogramming through promoting the MET and inhibiting c-Myc-dependent apoptosis.

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“…Previous work has established that TFAP2C regulates EGFR expression in both human and mouse models of the HER2-amplified breast cancer subtype (14). To determine whether similar mechanisms of regulation occur in luminal breast cancer, three ERα-positive luminal A cell lines were examined.…”

Section: Resultsmentioning

confidence: 99%

“…For example, vandetanib also has TKI activity against EGFR (13). Interestingly, it has recently been shown that EGFR is regulated by TFAP2C in HER2 breast cancer and neu -activated mouse mammary cancer (14). These findings generate several interesting questions.…”

Section: Introductionmentioning

confidence: 99%

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

Andrade

Park

et al. 2016

Molecular Cancer Therapeutics

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Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers and ChIP-seq confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, p < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, p < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated though the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.

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The role of Tcfap2c in tumorigenesis and cancer growth in an activated Neu model of mammary carcinogenesis

Cited by 24 publications

References 40 publications

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming

TFAP2C facilitates somatic cell reprogramming by inhibiting c-Myc-dependent apoptosis and promoting mesenchymal-to-epithelial transition

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

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