ZNF703

ZNF703[1] is a gene which has been linked with the development of breast cancers.[2][3][4] ZNF703 is contained within the NET/N1z family responsible for regulation of transcription essential for developmental growth especially in the hindbrain.[5] Normal functions performed by ZNF703 include adhesion, movement and proliferation of cells.[5] ZNF703 directly accumulates histone deacetylases at gene promoter regions but does not bind to functional DNA.[6]

zinc finger protein 703
Identifiers
SymbolZNF703
NCBI gene80139
HGNC25883
RefSeqNM_025069
Other data
LocusChr. 8 p12

Following research by scientists at Cancer Research UK, it was the first oncogene discovery in the past six years.[3]

ZNF703 is a part of 8p12 telomeric amplicon that is associated with Luminal B breast cancer. Recently, ZNF703 is identified as the driver of 8p12 locus amplification.[7]

Patients diagnosed with luminal B cancer caused by ZNF703 typically have lower recovery and survival rates than other cancer types.[8]

Drug resistance of ZNF703 has been displayed when patients are treated using anti-cancer drug Tamoxifen.[9]

Discovery

Researchers discovered the carcinogenic nature of ZNF703 in 2011 while conducting research on the classification and resistance of various oncogenes.[5] Researchers attempted to discern factors associated with various cancer types through observation of the oncogenic mechanism on a molecular scale.[5] The luminal B cancer pathway exhibited an amplification of 5 different genomic areas including the chromosome region 8p12.[5] Amplification of region 8p12 occurred through transcriptional regulation of ZNF703.[5]

Location
Oncogene ZNF703 is located at the p-arm of human chromosome 8 at position 8p12.

ZNF703 is located on human chromosome 8 at the short arm region commonly named chromosome region 8p12.[2] Tumors generated by ZNF703 have shown loss in size beginning at the telomere and ending at 8p12 while the 8p12-11 region has increased size.[10] A fluctuation between increase and decrease is present along the 8p12-8p21 boundary region of the chromosome.[10] A pattern has been found that involves three similar regions of disrupted growth and four regions of enhanced growth starting from the telomere and ending at the centromere.[10]

Role in cancer

The ZNF703 gene generally plays an active role in luminal B tumor cells contained in mammary ducts.[2] Typically, ZNF703 expression is greater when the tumors are estrogen receptor positive as opposed to estrogen receptor negative.[2] ZNF703 is co-expressed in a nuclear complex containing genes DCAF7, NCRO2 and PHB2.[2] ZNF703 generates a nuclear protein responsible for oestrogen receptor associated protein repression.[2] Gene expression of stem cells are triggered when the ZNF703 gene becomes overexpressed in the complex.[2] As a result, both regular cells and cancer stem cell abundance increases rapidly.[2] ZNF703 overexpression also causes primary and secondary tumorsphere development alongside amplified production of CD49F- positive cells associated with colon cancer.[2]

ZNF703 also experiences target regulation of cancer cells through the transcription of RNA SPRY4-It1.[11] RNA SPRY4-IT1 is a non-coding gene responsible for preventing apoptosis and generating large tumors.[11]

Researchers recently established a link between the trigger gene ZNF703 and Akt/mTOR pathway activation involved in the cellular cycle resulting in lung tumor formation.[12]

Prognosis

The lifespan of individuals with colorectal cancer and luminal cancer have different prognosis depending on the amount of expression of the ZNF703 gene.[8] Low amounts of transcription of ZNF703 usually leads to a healthier prognosis than individuals experiencing higher levels of transcription of the oncogene.[8] ZNF703 is a target for therapeutic medicines since survival rates increase as transcription rates decrease.[8]

Resistance to drugs

The drug Tamoxifen is a commonly administered drug used to treat luminal cancers in patients.[9] Half of patients treated with Tamoxifen are resistant to the drug.[9] Overexpression of ZNF703 has been linked to Tamoxifen resistance.[9] As transcription of the ZNF703 gene reaches substantial levels, instead of blocking cell proliferation, Tamoxifen is found to increase cancer cell division.[9] Tamoxifen can only be given at low dosages and patients are monitored daily in order to avoid tumor growth.[9]

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References
  1. http://www.ebi.ac.uk/gxa/gene?gid=Q9H7S9
  2. Sircoulomb F, Nicolas N, Ferrari A, et al. (February 2011). "ZNF703 gene amplification at 8p12 specifies luminal B breast cancer". EMBO Molecular Medicine. 3 (3): 153–166. doi:10.1002/emmm.201100121. PMC 3395112. PMID 21328542.
  3. "BBC News - Key breast cancer 'driver' gene found". 2011-02-18. Retrieved 2011-02-18.
  4. Kwek SS, Roy R, Zhou H, et al. (April 2009). "Co-amplified genes at 8p12 and 11q13 in breast tumors cooperate with two major pathways in oncogenesis". Oncogene. 28 (17): 1892–903. doi:10.1038/onc.2009.34. PMC 2722962. PMID 19330026.
  5. YANG, GONGLI; MA, FENG; ZHONG, MUXIAO; FANG, LIN; PENG, YAO; XIN, XIAOMING; ZHONG, JIETAO; YUAN, FANGFANG; GU, HONGXIANG (2014). "ZNF703 acts as an oncogene that promotes progression in gastric cancer". Oncology Reports. 31 (4): 1877–1882. doi:10.3892/or.2014.2997. PMID 24481460.
  6. Nakamura, Mako; Choe, Seong-Kyu; Runko, Alexander P.; Gardner, Paul D.; Sagerström, Charles G. (2008-11-12). "Nlz1/Znf703 acts as a repressor of transcription". BMC Developmental Biology. 8: 108. doi:10.1186/1471-213x-8-108. ISSN 1471-213X. PMC 2588584. PMID 19014486.
  7. Holland, Daniel (Feb 2011). "ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium". EMBO Molecular Medicine. 3 (3): 167–80. doi:10.1002/emmm.201100122. PMC 3395113. PMID 21337521.
  8. MA, FENG; BI, LIHONG; YANG, GONGLI; ZHANG, MENGNAN; LIU, CUIPING; ZHAO, YINGYING; WANG, YADONG; WANG, JIDE; BAI, YANG (2014). "ZNF703 promotes tumor cell proliferation and invasion and predicts poor prognosis in patients with colorectal cancer". Oncology Reports. 32 (3): 1071–1077. doi:10.3892/or.2014.3313. PMID 25017610.
  9. Zhang, Xi; Mu, Xin; Huang, Ou; Xie, Zuoquan; Jiang, Min; Geng, Meiyu; Shen, Kunwei (2013-08-26). "Luminal Breast Cancer Cell Lines Overexpressing ZNF703 Are Resistant to Tamoxifen through Activation of Akt/mTOR Signaling". PLOS ONE. 8 (8): e72053. doi:10.1371/journal.pone.0072053. ISSN 1932-6203. PMC 3753350. PMID 23991038.
  10. Gelsi-Boyer, Véronique; Orsetti, Béatrice; Cervera, Nathalie; Finetti, Pascal; Sircoulomb, Fabrice; Rougé, Carole; Lasorsa, Laurence; Letessier, Anne; Ginestier, Christophe (2005-12-01). "Comprehensive Profiling of 8p11-12 Amplification in Breast Cancer". Molecular Cancer Research. 3 (12): 655–667. doi:10.1158/1541-7786.mcr-05-0128. PMID 16380503.
  11. Shi, Yongguo; Li, Juan; Liu, Yangchen; Ding, Jie; Fan, Yingrui; Tian, Yun; Wang, Li; Lian, Yifan; Wang, Keming (2015-02-22). "The long noncoding RNA SPRY4-IT1 increases the proliferation of human breast cancer cells by upregulating ZNF703 expression". Molecular Cancer. 14: 51. doi:10.1186/s12943-015-0318-0. ISSN 1476-4598. PMC 4350857. PMID 25742952.
  12. Baykara, Onur; Dalay, Nejat; Kaynak, Kamil; Buyru, Nur (2016-10-01). "ZNF703 Overexpression may act as an oncogene in non-small cell lung cancer". Cancer Medicine. 5 (10): 2873–2878. doi:10.1002/cam4.847. ISSN 2045-7634. PMC 5083741. PMID 27650486.
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