Dear Maha,

The following text covers the answer to your question. In addition, please find two reviews: 1- "Milestones in the Discovery of HER2 Proto-Oncogene

and Trastuzumab (Herceptin™) " which illustrates the history of HER2 discovery and 2- "The oncogene HER2; Its signaling and transforming functions

and its role in human cancer pathogenesis " which might be helpful.

Receptor tyrosine-protein kinase erbB-2, also known as CD340 (cluster of differentiation 340), proto-oncogene Neu,Erbb2 (rodent), or ERBB2 (human) is a protein that in humans is encoded by the ERBB2 gene, which is also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu.

HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family. Amplification or overexpression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer. In recent years the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients.[1]

Name

HER2 is so 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. Molecular cloning of the gene showed that HER2, Neu, and ErbB-2 are all encoded by the same orthologs.[2]

Gene

ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12).

Function

The ErbB family is composed of four plasma membrane-bound receptor tyrosine kinases, the other members beingepidermal growth factor receptor, erbB-3 (neuregulin-binding; lacks kinase domain), and erbB-4. 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.[3]

Dimerisation results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways.

HER2 and cancer

Amplification or over-expression of the ERBB2 gene occurs in approximately 15-30% of breast cancers.[1][5] It is strongly associated with increased disease recurrence and a poor prognosis.[6] Over-expression is also known to occur in ovarian, stomach, and aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma.[7][8] eg. HER-2 is overexpressed in approximately 7-34% of patients with gastric cancer.[9] "22%"[10]

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.[11][12]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.[13]

HER2 variations/mutations

Furthermore, diverse structural alterations have been identified that cause ligand-independent firing of this receptor, doing so in the absence of receptor over-expression. HER2 is found in a variety of tumors and some of these tumors carry point mutations in the sequence specifying the transmembrane domain of HER2. Substitution of a valine for a glutamic acid in the transmembrane domain can result in the constitutive dimerization of this protein in the absence of a ligand.[citation needed]

HER2 mutations have been found in non-small-cell lung cancers (NSCLC) and can direct treatment.[14]

References:

Mitri Z, Constantine T, O'Regan R (2012). "The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy". Chemother Res Pract 2012: 743193. doi:10.1155/2012/743193. PMC 3539433. PMID 23320171.

Jump up ^ Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U (December 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.

Jump up ^ 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): 385–9. doi:10.1186/bcr327. PMC 138705. PMID 11737890.

Jump up ^ Roy V, Perez EA (November 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.

Jump up ^ Burstein HJ (October 2005). "The distinctive nature of HER2-positive breast cancers". N. Engl. J. Med. 353 (16): 1652–4. doi:10.1056/NEJMp058197. PMID 16236735.

Jump up ^ Tan M, Yu D (2007). "Molecular mechanisms of erbB2-mediated breast cancer chemoresistance". Adv. Exp. Med. Biol. 608: 119–29. doi:10.1007/978-0-387-74039-3_9. PMID 17993237.

Jump up ^ 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.

Jump up ^ Buza; et al. (2014). "HER2/neu in Endometrial Cancer: A Promising Therapeutic Target With Diagnostic Challenges.". Arch Pathol Lab Med. 2014 Mar;138(3):343-50 138: 343–50. doi:10.5858/arpa.2012-0416-RA. PMID 24576030.

Jump up ^ "HER2 testing in gastric cancer: a practical approach". Modern Pathology 25: 637–650. 2012. doi:10.1038/modpathol.2011.198.

Jump up ^ Judith Meza-Junco, Heather-Jane Au, Michael B Sawyer; Au; Sawyer (2011). "Critical appraisal of trastuzumab in treatment of advanced stomach cancer". Cancer Management and Research 2011 (3): 57–64. doi:10.2147/CMAR.S12698. PMC 3085240. PMID 21556317.

Jump up ^ Nagy P, Jenei A, Kirsch AK, Szöllosi J, Damjanovich S, Jovin TM (June 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.

Jump up ^ Kaufmann R, Müller P, Hildenbrand G, Hausmann M, Cremer C (April 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.

Jump up ^ Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Jänne PA (September 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.

Jump up ^ Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives.

Hoping this will be helpful,

Rafik

What exactly do you mean by 'location of mutation of Her2lneu sequence'? Do you have a specific point mutation in mind, such as L755W? Bear in mind that the name HER2/neu itself does not represent a mutated gene, but only the wild-type proto-oncogene. The gene only acquires oncogenic properties when it is amplified and/or mutated. There are several different driver mutations of HER2 and their genomic locations vary. Therefore you should specify which one of them you are interested in in order to know their exon number..

THANKS DR. Rafik Karaman for so many information i will discuss them with you latter that it my pleasure to get this response from you and thanks dr. Jaroslav Zak indeed my work in my hospital concentrated on IHC study so i would like to get an additional information about the detection of mutant type of HER2 /NEU   

kindly clarify your biological question so we can help you better. Her-2 is amplified in many cancer rather than mutated. There is also a soluble form that you can detect in serum or plasma. 

Her2 is on long arm of chromosome 17 (17q12–21.32) and in breast cancer is frequently amplified and rarely mutated

This paper might be of help for you. 

Defing Her2 overexpressionis important in tumor biology and in specific treatment with trastuzumab but it depends on presence of hormonal receptors. Another interesanting  fact is that Her2 status change during the treatment perhaps because of it.

thanks Eman and Edlira and Joe but i want information about the mutant type