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=== Gene ===
=== Gene ===
HER2 is encoded by ''ERBB2'', a known [[proto-oncogene]] located at the long arm of human [[chromosome 17]] (17q12). HER2 is named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent [[glioblastoma]] cell line, a type of neural tumor. ErbB-2 was named for its similarity to ''ERBB'' (avian erythroblastosis oncogene B), the [[oncogene]] later found to code for EGFR. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same [[gene]].<ref name="Coussens_1985">{{cite journal | author = Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U | title = Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene | journal = Science | volume = 230 | issue = 4730 | pages = 1132–9 | year = 1985 | month = December | pmid = 2999974 | doi = 10.1126/science.2999974 }}</ref>
HER2 is encoded by ''ERBB2'', a known [[proto-oncogene]] located at the long arm of human [[chromosome 17]] (17q12). HER2 is named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent [[glioblastoma]] cell line, a type of neural tumor. ErbB-2 was named for its similarity to ''ERBB'' (avian erythroblastosis oncogene B), the [[oncogene]] later found to code for [[Epidermal growth factor receptor | EGFR]]. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same [[gene]].<ref name="Coussens_1985">{{cite journal | author = Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U | title = Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene | journal = Science | volume = 230 | issue = 4730 | pages = 1132–9 | year = 1985 | month = December | pmid = 2999974 | doi = 10.1126/science.2999974 }}</ref>


=== Protein ===
=== Protein ===

Revision as of 11:07, 8 March 2013

Template:PBB HER2 (Human Epidermal Growth Factor Receptor 2) also known as Neu, ErbB-2, CD340 (cluster of differentiation 340) or p185 is a protein that in humans is encoded by the ERBB2 gene. HER2 is a member of the epidermal growth factor receptor (EGFR/ErbB) family. Amplification or over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain aggressive types of breast cancer and in recent years it has evolved to become an important biomarker and target of therapy for the disease.

Function

Gene

HER2 is encoded by ERBB2, a known proto-oncogene located at the long arm of human chromosome 17 (17q12). HER2 is named because it has a similar structure to human epidermal growth factor receptor, or HER1. Neu is so named because it was derived from a rodent glioblastoma cell line, a type of neural tumor. ErbB-2 was named for its similarity to ERBB (avian erythroblastosis oncogene B), the oncogene later found to code for EGFR. Gene cloning showed that HER2, Neu, and ErbB-2 are all encoded by the same gene.[1]

Protein

The ErbB family is composed of four plasma membrane-bound receptor tyrosine kinases. All four contain an extracellular ligand binding domain, a transmembrane domain, and an intracellular domain that can interact with a multitude of signaling molecules and exhibit both ligand-dependent and ligand-independent activity. HER2 can heterodimerise with any of the other three receptors and is considered to be the preferred dimerisation partner of the other ErbB receptors.[2] Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

Signal transduction

Signaling pathways activated by HER2 include:[3]

In summary, signaling through the ErbB family of receptors promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth from occurring.

HER2 and cancer

Amplification or over-expression of the ERBB2 gene occurs in approximately 30% of breast cancers. It is strongly associated with increased disease recurrence and a worse prognosis.[4] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.[5]

HER2 is co-localized, and, most of the time, co-amplified with the gene GRB7, which is a proto-oncogene associated with breast, testicular germ cell, gastric, and esophageal tumours.

HER2 proteins have been shown to form clusters in cell membranes that may play a role in tumorigenesis.[6][7]

Drugs targeting HER2

HER2 is the target of the monoclonal antibody trastuzumab (marketed as Herceptin). Trastuzumab is effective only in cancers where HER2 is over-expressed. An important downstream effect of trastuzumab binding to HER2 is an increase in p27, a protein that halts cell proliferation.[8] Another monoclonal antibody, Pertuzumab, which inhibits dimerization of HER2 and HER3 receptors, was approved by the FDA for use in combination with trastuzumab in June 2012.

Additionally, NeuVax (Galena Biopharma) is a peptide-based immunotherapy that directs "killer" T cells to target and destroy cancer cells that express HER2. It has entered phase 3 clinical trials.

It is revealed that patients with ER+ (Estrogen receptor positive)/HER2+ compared with ER-/HER2+ breast cancers may actually benefit more from drugs that inhibit the PI3K/AKT molecular pathway.[9]

Over-expression of HER2 can also be suppressed by the amplification of other genes. Research is currently being conducted to discover which genes may have this desired effect.

The expression of HER2 is regulated by signaling through estrogen receptors. Normally, estradiol and tamoxifen acting through the estrogen receptor down-regulate the expression of HER2. However, when the ratio of the coactivator AIB-3 exceeds that of the corepressor PAX2, the expression of HER2 is upregulated in the presence of tamoxifen, leading to tamoxifen-resistant breast cancer.[10][11]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[12]

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. As stated the HER2 is found in a variety of tumours and some of these tumours carry point mutations in the sequence specifying the transmembrane domain of HER2. The resulting substitution of a valine for a glutamic acid results in the constitutive dimerisation of this protein in the absence of a ligand.

Her2 and Her3 distribution on a breast cell, (3D Dual Colour Super Resolution Microscopy SPDMphymod / LIMON,marked with Alexa 488 and 568)

HER2 testing

HER2 testing is performed in breast cancer patients to assess prognosis and to determine suitability for Herceptin therapy. It is important that Herceptin is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.[13] For HER2-negative tumours, the risks of Herceptin clearly outweigh the benefits.

Tests are usually performed on biopsy samples obtained by either fine-needle aspiration, core needle biopsy, vacuum-assisted breast biopsy, or surgical excision. Immunohistochemistry is used to measure the amount of HER2 protein present in the sample. Alternatively, fluorescence in situ hybridisation (FISH) can be used to measure the number of copies of the gene which are present.

The extracellular domain of HER2 can be shed from the surface of tumour cells and enter the circulation. Measurement of serum HER2 by enzyme-linked immunosorbent assay (ELISA) offers a far less invasive method of determining HER2 status than a biopsy and consequently has been extensively investigated. Results so far have suggested that changes in serum HER2 concentrations may be useful in predicting response to Herceptin therapy.[14] However, its ability to determine eligibility for Herceptin therapy is less clear.[15]

HER2 interactions

HER2 has been shown to interact with Beta-catenin,[16][17][18] Glycoprotein 130,[19] PLCG1,[20][21] Erbin,[22][23][24] MUC1,[25][26] Grb2,[27][28][29] Heat shock protein 90kDa alpha (cytosolic), member A1,[30][31] DLG4,[32] PIK3R2,[33] PICK1[22] and SHC1.[27][29][34]

See also

References

  1. ^ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (1985). "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene". Science. 230 (4730): 1132–9. doi:10.1126/science.2999974. PMID 2999974. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Olayioye MA (2001). "Update on HER-2 as a target for cancer therapy: Intracellular signaling pathways of ErbB2/HER-2 and family members". Breast Cancer Res. 3 (6): 385–389. doi:10.1186/bcr327. PMC 138705. PMID 11737890.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Roy V, Perez EA (2009). "Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer". Oncologist. 14 (11): 1061–9. doi:10.1634/theoncologist.2009-0142. PMID 19887469. {{cite journal}}: Unknown parameter |month= ignored (help)
  4. ^ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Adv. Exp. Med. Biol. 608: 119–29. PMID 17993237.
  5. ^ Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. (2008). "Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu". Int J Gynaecol Obstet. 102 (2): 128–31. doi:10.1016/j.ijgo.2008.04.008. PMID 18555254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (1999). "Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy". J. Cell. Sci. 112 (11): 1733–41. PMID 10318765. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (2011). "Analysis of Her2/neu membrane protein clusters in different types of breast cancer cells using localization microscopy". J Microsc. 242 (1): 46–54. doi:10.1111/j.1365-2818.2010.03436.x. PMID 21118230. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ XF Le, Franz Pruefer, Robert Bast. (2005). "HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways". Cell Cycle. 4 (1): 87–95. doi:10.4161/cc.4.1.1360. PMID 15611642.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Loi S, Sotiriou C, Haibe-Kains B, Lallemand F, Conus NM, Piccart MJ, Speed TP, McArthur GA (2009). "Gene expression profiling identifies activated growth factor signaling in poor prognosis (Luminal-B) estrogen receptor positive breast cancer". BMC Med Genomics. 2: 37. doi:10.1186/1755-8794-2-37. PMC 2706265. PMID 19552798. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
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  11. ^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS (2008). "ERBB2 regulation by Estrogen Receptor-Pax2 determines tamoxifen response". Nature. 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Yonesaka K, Zejnullahu K, Okamoto I; et al. (2011). "Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab". Sci Transl Med. 3 (99): 99ra86. doi:10.1126/scitranslmed.3002442. PMC 3268675. PMID 21900593. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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  15. ^ Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (2009). "Utility of serum HER2 extracellular domain assessment in clinical decision making: pooled analysis of four trials of trastuzumab in metastatic breast cancer". J. Clin. Oncol. 27 (10): 1685–93. doi:10.1200/JCO.2008.16.8351. PMID 19255335. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Schroeder, Joyce A (2002). "ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas". J. Biol. Chem. 277 (25). United States: 22692–8. doi:10.1074/jbc.M201975200. ISSN 0021-9258. PMID 11950845. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  17. ^ Bonvini, P (2001). "Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription". Cancer Res. 61 (4). United States: 1671–7. ISSN 0008-5472. PMID 11245482. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  18. ^ Kanai, Y (1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin". Biochem. Biophys. Res. Commun. 208 (3). UNITED STATES: 1067–72. doi:10.1006/bbrc.1995.1443. ISSN 0006-291X. PMID 7702605. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  19. ^ Grant, Susan L (2002). "An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells". Oncogene. 21 (3). England: 460–74. doi:10.1038/sj.onc.1205100. ISSN 0950-9232. PMID 11821958. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  20. ^ Peles, E (1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. 10 (8). ENGLAND: 2077–86. ISSN 0261-4189. PMC 452891. PMID 1676673. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  21. ^ Arteaga, C L (1991). "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. 88 (23). UNITED STATES: 10435–9. doi:10.1073/pnas.88.23.10435. ISSN 0027-8424. PMC 52943. PMID 1683701. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  22. ^ a b Jaulin-Bastard, F (2001). "The ERBB2/HER2 receptor differentially interacts with ERBIN and PICK1 PSD-95/DLG/ZO-1 domain proteins". J. Biol. Chem. 276 (18). United States: 15256–63. doi:10.1074/jbc.M010032200. ISSN 0021-9258. PMID 11278603. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  23. ^ Borg, J P (2000). "ERBIN: a basolateral PDZ protein that interacts with the mammalian ERBB2/HER2 receptor". Nat. Cell Biol. 2 (7). ENGLAND: 407–14. doi:10.1038/35017038. ISSN 1465-7392. PMID 10878805. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  24. ^ Huang, Yang Z (2003). "Erbin suppresses the MAP kinase pathway". J. Biol. Chem. 278 (2). United States: 1108–14. doi:10.1074/jbc.M205413200. ISSN 0021-9258. PMID 12379659. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
  25. ^ Li, Yongqing (2003). "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein". Mol. Cancer Res. 1 (10). United States: 765–75. ISSN 1541-7786. PMID 12939402. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)
  26. ^ Schroeder, J A (2001). "Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland". J. Biol. Chem. 276 (16). United States: 13057–64. doi:10.1074/jbc.M011248200. ISSN 0021-9258. PMID 11278868. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysummary=, and |laysource= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help)CS1 maint: unflagged free DOI (link)
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Further reading

  • Ross JS, Fletcher JA, Linette GP; et al. (2003). "The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy". Oncologist. 8 (4): 307–25. doi:10.1634/theoncologist.8-4-307. PMID 12897328. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Zhou BP, Hung MC (2003). "Dysregulation of cellular signaling by HER2/neu in breast cancer". Semin. Oncol. 30 (5 Suppl 16): 38–48. doi:10.1053/j.seminoncol.2003.08.006. PMID 14613025.
  • Ménard S, Casalini P, Campiglio M; et al. (2005). "Role of HER2/neu in tumor progression and therapy". Cell. Mol. Life Sci. 61 (23): 2965–78. doi:10.1007/s00018-004-4277-7. PMID 15583858. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Becker JC, Muller-Tidow C, Serve H; et al. (2006). "Role of receptor tyrosine kinases in gastric cancer: new targets for a selective therapy". World J. Gastroenterol. 12 (21): 3297–305. PMID 16733844. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  • Laudadio J, Quigley DI, Tubbs R, Wolff DJ (2007). "HER2 testing: a review of detection methodologies and their clinical performance". Expert Rev. Mol. Diagn. 7 (1): 53–64. doi:10.1586/14737159.7.1.53. PMID 17187484.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Bianchi F, Tagliabue E, Ménard S, Campiglio M (2007). "Fhit expression protects against HER2-driven breast tumor development: unraveling the molecular interconnections". Cell Cycle. 6 (6): 643–6. doi:10.4161/cc.6.6.4033. PMID 17374991.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Del Bimbo A., Meoni M., Pala P. (2010). "Accurate evaluation of HER-2 amplification in FISH images". Imaging Systems and Techniques (IST), 2010 IEEE International Conference on: 407–10. doi:10.1109/IST.2010.5548461. ISBN 978-1-4244-6492-0.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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