{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nZNF703, a member of the NET/Nlz family of zinc finger transcription factors, has emerged as a novel oncogene particularly in luminal B breast cancers. Amplification of the gene in the 8p12 chromosomal region correlates with increased mRNA and protein expression that drives cell proliferation, enhances cancer stem cell properties, and contributes to resistance toward endocrine therapies (e.g., tamoxifen). Functional studies demonstrate that ZNF703 transforms fibroblasts, modulates TGFβ‐induced proliferation, and cooperates with key oncogenic pathways including Rb/E2F signaling and dominant-negative TP53, cumulatively contributing to poor clinical outcomes in these tumors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMechanistically, ZNF703 functions as a transcription regulator whose activity depends on its interaction with specific co-factors. In breast and other cancers, it has been identified as a co-factor within a nuclear complex (involving proteins such as DCAF7, PHB2, and NCOR2) that modulates the expression of stem cell–related genes and cell cycle regulators. In hepatocellular carcinoma, ZNF703 directly binds to the CLDN4 promoter to induce epithelial–mesenchymal transition (EMT) and metastasis, while in papillary thyroid carcinoma, it regulates key modulators including E2F1, MMP9, and p27 to influence proliferation, apoptosis, and invasion. Additional studies also highlight its role in activating the Akt/mTOR signaling pathway in non–small cell lung cancer, and structural analyses reveal that its conserved domains are essential for subcellular localization and transcriptional repression. These findings collectively underscore the multifaceted role of ZNF703 in transcription modulation and tumor progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond breast cancer, overexpression of ZNF703 has been implicated in a broad spectrum of malignancies. In gastric and colorectal cancers, elevated ZNF703 expression correlates with larger tumor size, advanced pathological stage, and increased metastatic potential, while experimental downregulation diminishes proliferation and migration. Similarly, in cholangiocarcinoma and head and neck squamous cell carcinoma, high levels of ZNF703 are associated with aggressive tumor behavior and poor prognosis. Moreover, studies in ovarian cancer further support its oncogenic role, and investigations using natural plant extracts demonstrate that reducing ZNF703 levels can induce apoptosis in cancer cells, thereby proposing this transcription factor as a promising therapeutic target across multiple tumor types."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel G Holland, Angela Burleigh, Anna Git, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Mol Med (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/emmm.201100122"}], "href": "https://doi.org/10.1002/emmm.201100122"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21337521"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21337521"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Fabrice Sircoulomb, Nathalie Nicolas, Anthony Ferrari, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2009.34"}], "href": "https://doi.org/10.1038/onc.2009.34"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19330026"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19330026"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xi Zhang, Xin Mu, Ou Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Luminal breast cancer cell lines overexpressing ZNF703 are resistant to tamoxifen through activation of Akt/mTOR signaling."}]}, {"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.0072053"}], "href": "https://doi.org/10.1371/journal.pone.0072053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23991038"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23991038"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Inga Reynisdottir, Adalgeir Arason, Berglind O Einarsdottir, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of ZNF703 independent of amplification indicates worse prognosis in patients with luminal B breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.88"}], "href": "https://doi.org/10.1002/cam4.88"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24156016"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24156016"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Elise Klæstad, Joanna Ewa Sawicka, Monica Jernberg Engstrøm, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 gene copy number and protein expression in breast cancer; associations with proliferation, prognosis and luminal subtypes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-020-06035-0"}], "href": "https://doi.org/10.1007/s10549-020-06035-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33389351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33389351"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Hao Wang, Hongfa Xu, Feng Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Zinc finger protein 703 induces EMT and sorafenib resistance in hepatocellular carcinoma by transactivating CLDN4 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-020-2422-3"}], "href": "https://doi.org/10.1038/s41419-020-2422-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32269215"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32269215"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Onur Baykara, Nejat Dalay, Kamil Kaynak, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 Overexpression may act as an oncogene in non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cam4.847"}], "href": "https://doi.org/10.1002/cam4.847"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27650486"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27650486"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Xiaolin Yang, Geling Liu, Luyang Zang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 is Overexpressed in Papillary Thyroid Carcinoma Tissues and Mediates K1 Cell Proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathol Oncol Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12253-018-0494-5"}], "href": "https://doi.org/10.1007/s12253-018-0494-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30361900"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30361900"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "J Wang, L-S Zhu, Y Luo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Transcription factor ZNF703 activates linc-UBC1 to stimulate the progression of glioma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Rev Med Pharmacol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.26355/eurrev_202003_20685"}], "href": "https://doi.org/10.26355/eurrev_202003_20685"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32271436"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32271436"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Isabel Pereira-Castro, Angela M Sousa Costa, Maria José Oliveira, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of human NLZ1/ZNF703 identifies conserved domains essential for proper subcellular localization and transcriptional repression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biochem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcb.24309"}], "href": "https://doi.org/10.1002/jcb.24309"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22886885"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22886885"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Gongli Yang, Feng Ma, Muxiao Zhong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 acts as an oncogene that promotes progression in gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2014.2997"}], "href": "https://doi.org/10.3892/or.2014.2997"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24481460"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24481460"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Feng Ma, Lihong Bi, Gongli Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 promotes tumor cell proliferation and invasion and predicts poor prognosis in patients with colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/or.2014.3313"}], "href": "https://doi.org/10.3892/or.2014.3313"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25017610"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25017610"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Keyu Li, Jiabei Wang, Jihua Han, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of ZNF703 facilitates tumorigenesis and predicts unfavorable prognosis in patients with cholangiocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.12627"}], "href": "https://doi.org/10.18632/oncotarget.12627"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27764785"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27764785"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Hang Yang, Wen-Qi Jiang, Ye Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elevated ZNF703 Protein Expression Is an Independent Unfavorable Prognostic Factor for Survival of the Patients with Head and Neck Squamous Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dis Markers (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2015/640263"}], "href": "https://doi.org/10.1155/2015/640263"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26063961"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26063961"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Ceren Orhan, Burak Bakır, Nejat Dalay, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 is an important player in head and neck cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Otolaryngol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/coa.13450"}], "href": "https://doi.org/10.1111/coa.13450"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31574205"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31574205"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Shuang Wang, Caixia Wang, Yuexin Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13046-020-01770-0"}], "href": "https://doi.org/10.1186/s13046-020-01770-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33246486"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33246486"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Elham Akbari Asl, Jalil Fallah Mehrabadi, Davoud Afshar, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Apoptotic Effects of Linum album Extracts on AGS Human Gastric Adenocarcinoma Cells and ZNF703 Oncogene Expression"}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Asian Pac J Cancer Prev (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.22034/APJCP.2018.19.10.2911"}], "href": "https://doi.org/10.22034/APJCP.2018.19.10.2911"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30362321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30362321"}]}]}]}