{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTFAP2C plays a pivotal role during early human development by governing lineage specification and chromatin remodeling. In pluripotent stem cells, TFAP2C is upregulated during the transition from the primed to naive state, where it occupies naive‐specific enhancers – including a novel enhancer regulating OCT4 – to maintain pluripotency and suppress neuroectodermal differentiation. In fetal gonocytes, TFAP2C (also known as AP-2γ) is expressed during critical windows of germ cell development and is retained in carcinoma in situ lesions, underscoring its oncofetal character. In addition, TFAP2C orchestrates epidermal differentiation by priming surface ectoderm chromatin and inducing p63 expression, and it is essential for extraembryonic development through the maintenance of trophoblast stem cells as well as proper placental lineage specification. Finally, TFAP2C-bound enhancers are necessary for establishing human primordial germ cell-like identity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn hormone-responsive breast cancers, TFAP2C emerges as a central regulator of cell fate and endocrine signaling. It directly drives the expression of estrogen receptor-α by binding to its promoter and cooperates with pioneer factors like FoxA1 to shape the chromatin landscape, thereby establishing and maintaining the luminal phenotype. Through regulation of a network of downstream targets—including crucial oncogenes and tumor suppressors such as ERBB2, GREB1, FOXA1, and even modulators of cell cycle checkpoints like p21—TFAP2C exerts context-dependent effects that can either restrain or promote cell proliferation. Moreover, its expression is linked to late poor outcomes in ER-positive patients and defines a genetic dependency in certain HER2-amplified cancers, pinpointing TFAP2C as a promising therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond development and breast carcinogenesis, TFAP2C influences tumor progression and cellular behavior in diverse malignancies. In malignant melanoma, TFAP2C functions as a tumor suppressor, with its dysregulation—mediated in part by microRNA networks—affecting cell migration and metastasis through regulation of extracellular matrix components such as ECM1. In non-small cell lung cancer, aberrant TFAP2C overexpression promotes cell cycle progression and tumorigenesis via upregulation of TGFBR1 and activation of PAK1 signaling pathways, while miR-137 induction by EMT regulators leads to its downregulation and enhanced metastatic potential. In seminomas, m6A-dependent stabilization of TFAP2C mRNA facilitates DNA repair gene upregulation, contributing to cisplatin resistance. In addition, TFAP2C modulates cellular motility by controlling RND3 expression, thereby influencing cell collision guidance and extracellular matrix anisotropy. Finally, its involvement in restraining trophoblast invasion suggests a role in the pathogenesis of preeclampsia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "William A Pastor, Wanlu Liu, Di Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C regulates transcription in human naive pluripotency by opening enhancers."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41556-018-0089-0"}], "href": "https://doi.org/10.1038/s41556-018-0089-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29695788"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29695788"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Katharina Pauls, Richard Jäger, Susanne Weber, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor AP-2gamma, a novel marker of gonocytes and seminomatous germ cell tumors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.20913"}], "href": "https://doi.org/10.1002/ijc.20913"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15700319"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15700319"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Lingjie Li, Yong Wang, Jessica L Torkelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C- and p63-Dependent Networks Sequentially Rearrange Chromatin Landscapes to Drive Human Epidermal Lineage Commitment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2018.12.012"}], "href": "https://doi.org/10.1016/j.stem.2018.12.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30686763"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30686763"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Peter Kuckenberg, Caroline Kubaczka, Hubert Schorle "}, {"type": "b", "children": [{"type": "t", "text": "The role of transcription factor Tcfap2c/TFAP2C in trophectoderm development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Reprod Biomed Online (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.rbmo.2012.02.015"}], "href": "https://doi.org/10.1016/j.rbmo.2012.02.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22560121"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22560121"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Di Chen, Wanlu Liu, Jill Zimmerman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2018.12.011"}], "href": "https://doi.org/10.1016/j.celrep.2018.12.011"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30590035"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30590035"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Si Kee Tan, Zhen Hua Lin, Cheng Wei Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.151"}], "href": "https://doi.org/10.1038/emboj.2011.151"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21572391"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21572391"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "George W Woodfield, Yizhen Chen, Thomas B Bair, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of primary gene targets of TFAP2C in hormone responsive breast carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Chromosomes Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/gcc.20807"}], "href": "https://doi.org/10.1002/gcc.20807"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20629094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20629094"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "George W Woodfield, Annamarie D Horan, Yizhen Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C controls hormone response in breast cancer cells through multiple pathways of estrogen signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-07-2293"}], "href": "https://doi.org/10.1158/0008-5472.CAN-07-2293"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17875680"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17875680"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "A R Cyr, M V Kulak, J M Park, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2013.569"}], "href": "https://doi.org/10.1038/onc.2013.569"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24469049"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24469049"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Susan M Perkins, Casey Bales, Tudor Vladislav, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C expression in breast cancer: correlation with overall survival beyond 10 years of initial diagnosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-015-3492-2"}], "href": "https://doi.org/10.1007/s10549-015-3492-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26160249"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26160249"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "K-K Shiu, D Wetterskog, A Mackay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrative molecular and functional profiling of ERBB2-amplified breast cancers identifies new genetic dependencies."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2012.625"}], "href": "https://doi.org/10.1038/onc.2012.625"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23334330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23334330"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Philip M Spanheimer, Anthony R Cyr, Matthew P Gillum, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Distinct pathways regulated by RET and estrogen receptor in luminal breast cancer demonstrate the biological basis for combination therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Surg (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/SLA.0b013e3182a6f552"}], "href": "https://doi.org/10.1097/SLA.0b013e3182a6f552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24045439"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24045439"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Minxing Ma, Dong Guo, Zengqi Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Fucosyltransferase 8 regulation and breast cancer suppression by transcription factor activator protein 2γ."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.14987"}], "href": "https://doi.org/10.1111/cas.14987"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34036684"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34036684"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Ping-Pui Wong, Fabrizio Miranda, KaYi V Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Histone demethylase KDM5B collaborates with TFAP2C and Myc to repress the cell cycle inhibitor p21(cip) (CDKN1A)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.06373-11"}], "href": "https://doi.org/10.1128/MCB.06373-11"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22371483"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22371483"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Elisa Penna, Francesca Orso, Daniela Cimino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "microRNA-214 contributes to melanoma tumour progression through suppression of TFAP2C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2011.102"}], "href": "https://doi.org/10.1038/emboj.2011.102"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21468029"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21468029"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Wanyeon Kim, EunGi Kim, Sungmin Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial-mesenchymal transition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Mol Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emm.2016.125"}], "href": "https://doi.org/10.1038/emm.2016.125"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27885255"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27885255"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "J Kang, W Kim, S Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2016.328"}], "href": "https://doi.org/10.1038/onc.2016.328"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27593936"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27593936"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Tzu-Hua Chang, Meng-Feng Tsai, Chien-Hung Gow, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Upregulation of microRNA-137 expression by Slug promotes tumor invasion and metastasis of non-small cell lung cancer cells through suppression of TFAP2C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2017.06.002"}], "href": "https://doi.org/10.1016/j.canlet.2017.06.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28610956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28610956"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Jingchao Wei, Yinghao Yin, Jun Zhou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "METTL3 potentiates resistance to cisplatin through m"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "6"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " A modification of TFAP2C in seminoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15738"}], "href": "https://doi.org/10.1111/jcmm.15738"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32857912"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32857912"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Geeta Lal, Piedad Gomez Contreras, Mikhail Kulak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human Melanoma cells over-express extracellular matrix 1 (ECM1) which is regulated by TFAP2C."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0073953"}], "href": "https://doi.org/10.1371/journal.pone.0073953"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24023917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24023917"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Danielle Park, Esther Wershof, Stefan Boeing, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extracellular matrix anisotropy is determined by TFAP2C-dependent regulation of cell collisions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Mater (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41563-019-0504-3"}], "href": "https://doi.org/10.1038/s41563-019-0504-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31659294"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31659294"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Tomomi Kotani, Akira Iwase, Kazuhiko Ino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activator protein-2 impairs the invasion of a human extravillous trophoblast cell line."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2008-1645"}], "href": "https://doi.org/10.1210/en.2008-1645"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19443578"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19443578"}]}]}]}