ヒト上皮細胞成長因子受容体2, human epidermal growth factor receptor 2

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/12 23:05:42」(JST)

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HER2の細胞外ドメインとトラスツズマブの複合体の構造。

HER2の細胞外ドメインとペルツズマブの複合体の構造。トラスツズマブと異なり、第IIドメインに結合し、HER2の二量体化を防ぐ。

HER2（ハーツー）は、細胞表面に存在する約185 kDaの糖タンパクで、受容体型チロシンキナーゼである。上皮成長因子受容体 (EGFR、別名ERBB1) に類似した構造をもち、EGFR2、ERBB2、CD340、あるいはNEUとも呼ばれる。HER2タンパクをコードする遺伝子は HER2/neu、erbB-2 で17番染色体長腕に存在する。また、HER2 は、human epidermal growth factor receptor (HER/EGFR/ERBB) family(EGFファミリー)に属するタンパク質である。

HER2タンパクは正常細胞において細胞の増殖、分化などの調節に関与しているが、何らかの理由でHER2遺伝子の増幅や遺伝子変異が起こると、細胞の増殖・分化の制御ができなくなり、細胞は悪性化する。HER2遺伝子はがん遺伝子でもあり、多くの種類のがんで遺伝子増幅がみられる。

1 発見の歴史
2 機能
3 遺伝子
4 悪性腫瘍におけるHER2
5 HER検査の評価法
- 5.1 IHC法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）
- 5.2 FISH法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）
- 5.3 HER2蛋白および遺伝子の検査キット
6 HER2を標的にした治療
- 6.1 トラスツズマブ
- 6.2 ペルツズマブ
7 参考文献
8 外部リンク

発見の歴史

1985年、ヒトEGFRに類似した受容体型チロシンキナーゼがクローニングされ、ヒトEGFR関連物質2 human EGFR-related 2 の略よりHER2と名付けられた^[1]。このHER2をコードする遺伝子は、ラットの神経膠芽腫 neuroglioblastoma 細胞株から見つかったがん遺伝子 neu に一致しており、同一のものと考えられた^[1]。

また同時期、ヒト乳癌細胞や唾液腺腺癌で、トリ赤芽球症ウイルス avian erythroblastic leukemia virus のもつがん遺伝子 v-erbB に類似した遺伝子が増幅していることが発見された。ヒトEGFR遺伝子が v-erbBと相同性が高いことは知られていたが、この新たな遺伝子はEGFR遺伝子とは別個のものであり、ヒトEGFR遺伝子はc-erbB-1、この新たな遺伝子はc-erbB-2 と名付けられた。またこれは neu と同じものであることが確認された^[2]^[3]。1986年 c-erbB-2遺伝子産物がチロシンキナーゼ活性を持った185 kDaの糖タンパクであることが確認された^[4]。

機能

HER2は心臓や神経の発達や維持に関与し、その他の細胞でも細胞増殖、分化などの調節に関与している。HER2遺伝子を人為的に欠失させたマウスは、心臓や神経系の発達障害により胎生期に死亡する^[5]。また出生後に心筋のHER2遺伝子発現を人為的に低下させたマウスは拡張型心筋症を呈した^[6]^[7]。同様に腸管の神経のHER2遺伝子発現を人為的に低下させたマウスは、腸管の発育不良、腸管拡張をおこし、ヒトヒルシュスプルング病に類似した病態を呈した^[8]。

HER2タンパクは受容体型チロシンキナーゼである。同じEGFRファミリーに属するHER1, HER3, HER4 は細胞外領域にligandが結合することにより３次元構造が変化して他のHER family との二量体形成が可能となる。しかしHER2に結合する内因性リガンドは知られていない。ホモ二量体あるいは活性化したEGFR（HER1)やHER3、HER4と結合してヘテロ二量体を形成しシグナル伝達を行うと考えられている^[9]。このほかHER2 shedding (蛋白分解酵素によって細胞外ドメインECDが切断されること）によって残される細胞内領域と膜貫通領域からなる95kDの蛋白断片p95も増殖シグナル活性がある^[10]。HER2 shedding を引き起こす蛋白分解酵素は亜鉛含有メタロプロテアーゼと推定されている。

遺伝子

ヒトHER2をコードする遺伝子は、17番染色体長腕 (17q11.2-q12; 17q21.1) に存在する^[11]。

悪性腫瘍におけるHER2

HER2は正常細胞では、増殖、分化、移動、生存などの細胞機能調節に関与している。何らかの理由でHER2遺伝子に増幅や変異が起こると下流のシグナル伝達経路が活性化し、がん遺伝子として働く。唾液腺腺癌^[2]、胃癌、乳癌、卵巣癌^[12]等多くのがんでHER2の遺伝子増幅がみられる。

またHER2タンパクを過剰発現する乳癌・卵巣癌は予後不良である^[12]。ただし、これはHER2タンパクを標的とした治療を行う以前の話である。

HER検査の評価法

HER2検査には、HERタンパク質の過剰発現を調べる免疫組織化学（IHC)法と、HER2遺伝子の増幅を調べる蛍光in situ hybridization （FISH)法がある。検査対象は原発巣あるいは転移巣のホルマリン固定・パラフィン包埋組織標本である。固定は10％中性緩衝ホルマリンで6時間以上48時間までが推奨される。

IHC法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）

スコア	所見
0	細胞膜染色なし、または10％未満の癌細胞の膜に染色
1+	10％以上の癌細胞の膜に不完全な染色
2+	10％以上の癌細胞の膜に弱～中等度の完全な染色または、10％以上30％以下の癌細胞の膜に強度の完全な染色
3+	30％を超える癌細胞の膜に強度の完全な染色

FISH法によるHER2検査の判定スコア(2007 ASCO/CAPガイドライン）

判定	FISHの結果
陰性	HER2/17cen(CEP17)比1.8未満
境界域	HER2/17cen(CEP17)比1.8～2.2
陽性	HER2/17cen(CEP17)比＞2.2

癌細胞の核を20個測定する。 ^[13]

HER2蛋白および遺伝子の検査キット

検査法	標的	検査対象	キット名	製造元／販売会社
免疫組織化学法	蛋白	癌組織	ダコHercep Test　ヒストファインHer2キット　ベンタナパスウェイHER2　協和ステインHER2/neu	ダコ・ジャパン　ニチレイ　ロッシュ・ダイアグノステイクス　協和メデイクス
FISH法	DNA	癌組織	パスビジョンHER-2 DNA プローベキット　ヒストラHER2 FISHキット	アボットジャパン　常光
CLEIA	蛋白	血液、乳頭分泌物、組織抽出液	ケミルミADVIA Centaur CP	シーメンス

CLEA: chemiluminescence enzyme immunoassay ^[14]

HER2を標的にした治療

HER2タンパクを標的とした分子標的治療薬に、トラスツズマブやペルツズマブがある。

トラスツズマブ

詳細はトラスツズマブを参照。

トラスツズマブ（ハーセプチン^®）はHER2タンパクに結合するモノクローナル抗体である。主にHER2タンパクを発現する乳癌に対する治療薬として用いられる^[15]。なお、治験段階における乳癌患者や医師らの苦悩の末に、ハーセプチン^®が乳癌治療薬としてFDAにより認可されるに至る、その険しい道のりを描いたノンフィクションに、映画『希望のちから』（原題：en:Living Proof (film)）がある。

ペルツズマブ

ペルツズマブは、トラスツズマブと同様HER2に結合する抗体であるが、トラスツズマブと異なるところに結合し、HER2の二量体化を防ぐ点が異なる。この薬剤は現在、臨床試験が進行中である。

参考文献

^ ^a ^b Coussens L, Yang-Feng TL, Liao YC, et al. "Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene." Science, Vol.230, No.4730, 1985, p.p. 1132-1139. PMID 2999974
^ ^a ^b Semba K, Kamata N, Toyoshima K, et al. "A v-erbB-related protooncogene, c-erbB-2, is distinct from the c-erbB-1/epidermal growth factor-receptor gene and is amplified in a human salivary gland adenocarcinoma." Proceedings of National Academy of Science of United States of America, Vol.82, No.19, 1985, p.p. 6497-6501. PMID 2995967
^ King CR, Kraus MH, Saronson SA. "Amplification of a novel v-erbB-related gene in a human mammary carcinoma." Science, Vol.229, No.4717, 1985, p.p. 974-976. PMID 2992089
^ Akiyama T, Sudo C, Ogawara H, et al. "The product of the human c-erbB-2 gene: a 185-kilodalton glycoprotein with tyrosine kinase activity." Science, Vol.232, No.4758, 1986, p.p. 1644-1646. PMID 3012781
^ Lee KF, Simon H, Chen H, et al. "Requirement for neuregulin receptor erbB2 in neural and cardiac development." Science, Vol.378, No.6555, 1995, p.p. 394-398. PMID 7477377
^ Crone SA, Zhao YY, Fan L, et al. "ErbB2 is essential in the prevention of dilated cardiomyopathy." Nature Medicine, Vol.8, No.5, 2002, p.p. 459-465. PMID 11984589
^ Ozcelik C, Erdmann B, Pilz B, et al. "Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy." Proceedings of National Academy of Science of United States of America, Vol.99, Bo.13, 2002, p.p. 8880-8885. PMID 12072561
^ Crone SA, Negro A, Trumpp A, et al. "Colonic epithelial expression of ErbB2 is required for postnatal maintenance of the enteric nervous system." Neuron, Vol.37, No.1, p.p. 29-40. PMID 12526770
^ Graus-Porta D, Beerli RR, Daly JM, Hynes NE. "ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling." EMBO Journal, Vol.16, No.7, 1997, p.p. 1647-1655. PMID 9130710
^ Tse C, Gauchez A, Jacot W, Lamy P. HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer Cancer Treatment Reviews 2011
^ ERBB2 - Entrez Gene
^ ^a ^b Slamon DJ, Clark GM, Wong SG, et al. "Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene." Science, Vol.235, No.4785, 1987, p.p. 177-182. PMID 3798106
^ American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF; American Society of Clinical Oncology/College of American Pathologists. Arch Pathol Lab Med. 2007;131(1):18-43.
^ 熊木伸枝、梅村しのぶ「HER2の検索法と陽性の基準」　戸井雅和編「みんなに役立つ乳癌の基礎と臨床」p372
^ Slamon DJ, Leyland-Jones B, Shak S, et al. "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2." NEJM., Vol.344, No.11, 2001, p.p. 783-792. PMID 11248153

外部リンク

Her2シグナルパスウェイ

wiki en

[Wiki en表示]

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 being epidermal 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.

Signal transduction

Signaling pathways activated by HER2 include:^[4]

mitogen-activated protein kinase (MAPK)
phosphoinositide 3-kinase (PI3K/Akt)
phospholipase C γ
protein kinase C (PKC)
Signal transducer and activator of transcription (STAT)

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 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]

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.^[8]^[9]

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.

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.^[10] 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 has been found 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.^[11]

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.^[12]^[13]

Recent evidence has implicated HER2 signaling in resistance to the EGFR-targeted cancer drug cetuximab.^[14]

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 trastazumab therapy. It is important that trastazumab is restricted to HER2-positive individuals as it is expensive and has been associated with cardiac toxicity.^[15] For HER2-negative tumours, the risks of trastazumab clearly outweigh the benefits.

HER2 testing on tumor

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.

HER2 testing on serum

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 trastazumab therapy.^[16] However, its ability to determine eligibility for trastazumab therapy is less clear.^[17]

HER2 interactions

HER2/neu has been shown to interact with:

CTNNB1,^[18]^[19]^[20]
DLG4,^[21]
Erbin,^[22]^[23]^[24]
GRB2,^[25]^[26]^[27]
HSP90AA1,^[28]^[29]
IL6ST,^[30]
MUC1,^[31]^[32]
PICK1^[22] and
PIK3R2,^[33]
PLCG1,^[34]^[35] and
SHC1.^[25]^[27]^[36]

References

^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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 ( Pt 11) (11): 1733–41. PMID 10318765.
^ 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.
^ Le XF, Pruefer F, Bast RC (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.
^ 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. Lay summary – ScienceDaily.
^ "Study sheds new light on tamoxifen resistance". Cordis News. Cordis. 2008-11-13. Retrieved 2008-11-14.
^ Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS (November 2008). "Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen". Nature 456 (7222): 663–6. doi:10.1038/nature07483. PMC 2920208. PMID 19005469.
^ 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.
^ Telli ML, Hunt SA, Carlson RW, Guardino AE (August 2007). "Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility". J. Clin. Oncol. 25 (23): 3525–33. doi:10.1200/JCO.2007.11.0106. PMID 17687157.
^ Ali SM, Carney WP, Esteva FJ, Fornier M, Harris L, Köstler WJ, Lotz JP, Luftner D, Pichon MF, Lipton A (September 2008). "Serum HER-2/neu and relative resistance to trastuzumab-based therapy in patients with metastatic breast cancer". Cancer 113 (6): 1294–301. doi:10.1002/cncr.23689. PMID 18661530.
^ Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B (April 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.
^ Schroeder JA, Adriance MC, McConnell EJ, Thompson MC, Pockaj B, Gendler SJ (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): 22692–8. doi:10.1074/jbc.M201975200. PMID 11950845.
^ Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, Dunach M, Neckers LM (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): 1671–7. PMID 11245482.
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External links

ERBB2 expression across human cancerous and healthy tissues
AACR Cancer Concepts Factsheet on HER2
Her2/neu Vaccine Protects Against Tumor Growth
Chimeric molecules and Methods of Use
Breast Friends for Life Network - A South African Breast Cancer Support Forum for HER2 Positive Women
HerceptinR : Herceptin Resistance Database for Understanding Mechanism of Resistance in Breast Cancer Patients. Sci. Rep. 4:4483
Receptor, erbB-2 at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. 乳癌におけるHER2と治療の効果予測 her2 and predicting response to therapy in breast cancer
2. HER2陽性乳癌に対する補助化学療法 adjuvant medical therapy for her2 positive breast cancer
3. HER2陽性転移性乳癌の全身治療 systemic treatment for her2 positive metastatic breast cancer
4. トラスツズマブおよびその他の抗HER2薬の心毒性 cardiotoxicity of trastuzumab and other her2 targeted agents
5. 限局性初期乳癌における予後予測因子 prognostic and predictive factors in early non metastatic breast cancer

English Journal

Prognostic factors and outcome analysis of salivary duct carcinoma.

Han MW1, Roh JL2, Choi SH2, Nam SY2, Lee HJ3, Cho KJ3, Lee SW4, Kim SY5.
Auris, nasus, larynx.Auris Nasus Larynx.2015 Dec;42(6):472-7. doi: 10.1016/j.anl.2015.04.005. Epub 2015 May 28.
OBJECTIVE: Salivary duct carcinoma (SDC) is highly aggressive, with high rates of recurrence and nodal and distant metastases. The aim of the current study was to evaluate the clinical implication of EGFR and HER2 expression for predicting prognosis and to identify the factors associated with outcom
PMID 26028371

A label-free electrochemical affisensor for cancer marker detection: The case of HER2.

Ravalli A1, da Rocha CG2, Yamanaka H3, Marrazza G4.
Bioelectrochemistry (Amsterdam, Netherlands).Bioelectrochemistry.2015 Dec;106(Pt B):268-75. doi: 10.1016/j.bioelechem.2015.07.010. Epub 2015 Aug 3.
In this paper, we report the development of a sensitive label-free impedimetric biosensor based on the use of affibody as bioreceptor and gold nanostructured screen-printed graphite as a sensor platform for the detection of human epidermal growth factor receptor 2 (HER2). The affisensor is realized
PMID 26260578

ErbB-2 signaling plays a critical role in regulating androgen-sensitive and castration-resistant androgen receptor-positive prostate cancer cells.

Muniyan S1, Chen SJ1, Lin FF1, Wang Z1, Mehta PP1, Batra SK2, Lin MF3.
Cellular signalling.Cell Signal.2015 Nov;27(11):2261-71. doi: 10.1016/j.cellsig.2015.08.002. Epub 2015 Aug 6.
While androgen deprivation therapy (ADT) reduces tumor burden, autocrine growth factor loops such as human epidermal growth factor receptor 2 (HER2/ErbB-2/neu) have been proposed to contribute to prostate cancer (PCa) survival and relapse. However, the role of ErbB-2 in regulating androgen-sensitive
PMID 26257301

Japanese Journal

切除不能・進行再発胃がん (特集消化器がん診療の最前線 : 適切な診療を行うためのエッセンス) -- (消化器がん診療各論)

工藤敏啓,坂井大介,佐藤太郎
内科 114(4), 593-596, 2014-10
NAID 40020213245

進行再発乳がんの抗HER2療法パージェタ、カドサイラ登場で、1~2次治療に大きな変化新薬の登場で、HER2陽性・進行再発乳がん治療はここまで変わった! (乳がん最新大特集)

柄川昭彦 [取材・文]
がんサポート 12(11), 28-31, 2014-10
NAID 40020211796

症例骨髄がん腫症で発症したHER2陽性乳がんの1例

土井美帆子
腫瘍内科 14(3), 294-299, 2014-09
NAID 40020220565

Related Pictures

★リンクテーブル★

国試過去問	「106A036」「109D006」
リンク元	「トラスツズマブBS」「トリプルネガティブ乳癌」「ヒト上皮細胞成長因子受容体2」「human epidermal growth factor receptor 2」「c-erbB2」
拡張検索	「HER2/neu」「HER2遺伝子」

「106A036」

Erb-b2 receptor tyrosine kinase 2
	PDB rendering based on 1n8z.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1MFG, 1MFL, 1MW4, 1N8Z, 1OVC, 1QR1, 1S78, 2A91, 2JWA, 2KS1, 2L4K, 3BE1, 3H3B, 3MZW, 3N85, 3PP0, 3RCD, 3WSQ, 4GFU, 4HRL, 4HRM, 4HRN
Identifiers
Symbols	ERBB2 ; CD340; HER-2; HER-2/neu; HER2; MLN 19; NEU; NGL; TKR1
External IDs	OMIM: 164870 MGI: 95410 HomoloGene: 3273 ChEMBL: 1824 GeneCards: ERBB2 Gene
EC number	2.7.10.1
Gene ontology
Molecular function	• RNA polymerase I core binding; • protein tyrosine kinase activity; • transmembrane receptor protein tyrosine kinase activity; • receptor signaling protein tyrosine kinase activity; • transmembrane signaling receptor activity; • protein binding; • ATP binding; • protein C-terminus binding; • growth factor binding; • protein phosphatase binding; • identical protein binding; • ErbB-3 class receptor binding; • protein heterodimerization activity; • protein dimerization activity;
Cellular component	• nucleus; • cytoplasm; • plasma membrane; • endosome membrane; • integral component of membrane; • basolateral plasma membrane; • apical plasma membrane; • cytoplasmic vesicle; • myelin sheath; • receptor complex; • perinuclear region of cytoplasm;
Biological process	• positive regulation of protein phosphorylation; • transcription, DNA-templated; • protein phosphorylation; • signal transduction; • cell surface receptor signaling pathway; • enzyme linked receptor protein signaling pathway; • transmembrane receptor protein tyrosine kinase signaling pathway; • epidermal growth factor receptor signaling pathway; • axon guidance; • peripheral nervous system development; • heart development; • neuromuscular junction development; • motor neuron axon guidance; • cell proliferation; • fibroblast growth factor receptor signaling pathway; • phosphatidylinositol 3-kinase signaling; • peptidyl-tyrosine phosphorylation; • signal transduction by protein phosphorylation; • positive regulation of cell growth; • regulation of microtubule-based process; • negative regulation of immature T cell proliferation in thymus; • Fc-epsilon receptor signaling pathway; • wound healing; • myelination; • positive regulation of MAP kinase activity; • positive regulation of GTPase activity; • innate immune response; • positive regulation of translation; • regulation of angiogenesis; • positive regulation of cell adhesion; • positive regulation of transcription from RNA polymerase I promoter; • positive regulation of transcription from RNA polymerase III promoter; • protein autophosphorylation; • neurotrophin TRK receptor signaling pathway; • phosphatidylinositol-mediated signaling; • oligodendrocyte differentiation; • positive regulation of epithelial cell proliferation; • regulation of ERK1 and ERK2 cascade;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

48歳の女性。 1か月前からの全身倦怠感を主訴に来院した。 42歳時に右乳癌の治療を受けている。乳癌はエストロゲン受容体陰性、 HER2陰性であった。
身長158cm、体重54kg。体温36.4℃。脈拍72/分、整。血圧120/60mmHg。眼球結膜に黄染を認めない。腹部は平坦、軟で、右肋骨弓下に肝の辺縁を触知する。
血液所見:赤血球324万、 Hb9.6g/dl、 Ht34%、白血球6,700、血小板36万。血液生化学所見:総蛋白6.8g/dl、アルブミン4.0g/dl、尿素窒素16mg/dl、クレアチニン0.7mg/dl、総ビリルビン0.6mg/dl、 AST68IU/l、 ALT80IU/l。 CA15-3 150U/ml(基準30以下)。腹部造影CT(別冊No. 13)を別に示す。治療として適切なのはどれか。