ERBB3

Official Full Name

erb-b2 receptor tyrosine kinase 3

Organism

Homo sapiens

GeneID

2065

Background

This gene encodes a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. This membrane-bound protein has a neuregulin binding domain but not an active kinase domain. It therefore can bind this ligand but not convey the signal into the cell through protein phosphorylation. However, it does form heterodimers with other EGF receptor family members which do have kinase activity. Heterodimerization leads to the activation of pathways which lead to cell proliferation or differentiation. Amplification of this gene and/or overexpression of its protein have been reported in numerous cancers, including prostate, bladder, and breast tumors. Alternate transcriptional splice variants encoding different isoforms have been characterized. One isoform lacks the intermembrane region and is secreted outside the cell. This form acts to modulate the activity of the membrane-bound form. Additional splice variants have also been reported, but they have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

Synonyms

HER3; FERLK; LCCS2; VSCN1; ErbB-3; c-erbB3; erbB3-S; MDA-BF-1; c-erbB-3; p180-ErbB3; p45-sErbB3; p85-sErbB3;

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Detailed Information

The ErbB family plays an important role in promoting tumor formation and growth. Its receptor structure is mainly composed of extracellular region, α-helical transmembrane segment and intracellular protein tyrosinase region which mediates intramolecular signaling, and is widely expressed in epithelial cells, mesenchymal cells, cardiomyocytes and nerve cells. . At the same time, it involves the process of proliferation, survival, angiogenesis and metastasis of tumor cells.The structure of ErbB3 in the ErbB family is different. It does not form dimers and the activity of intracellular tyrosine kinase (TK) is less and the catalytic activity is not high. It forms a heterodimer by binding to a ligand, heregulin (HRG) or neuregulin (NRG), and attracts a receptor containing TK activity to activate TK. When mediating cell signaling, ErbB3 must phosphorylate by interacting with other cytokines to promote tumor proliferation, of which ErbB2 is the most important member.

ErbB3 Figure 1. Current and novel therapeutic strategies targeting of erbB2 and/or erbB3 receptors for cancer therapy. (Ma, J. et al. 2014)

Progress in Targeted Therapy of ErbB3 with Common Tumors

The lack of tumor biomarkers is a major obstacle to the early diagnosis and treatment of malignant tumors. E3 ubiquitin ligase, monoclonal antibodies, and microRNAs (miRNAs) are the major molecular markers currently regulating ErbB3 expression and function.ErbB3 is highly expressed in common tumors such as breast cancer, melanoma, and pancreatic cancer, and can cause resistance to various cancer treatments when activated. ErbB3 activates the PI-3K/AKT, Jak/Stat signaling pathway and produces drug resistance to the treatment of non-small cell lung cancer (NSCLC) and colon cancer.

In the targeted therapy of NSCLC, the ErbB3 binding protein p42 inhibits the activation of the AKT pathway and the overexpression of the activated pathway, thereby inhibiting cell proliferation, non-adherent growth and invasion, and tumor growth in vivo. ErbB3-specific antibody AMG888 in combination with radiotherapy promotes DNA damage and cell death in NSCLC cells and inhibits tumor growth. The NSCLC xenograft model is resistant to cetuximab and small molecule kinase inhibitors, and the use of MM121 antibody restores the therapeutic effect of cetuximab on tumors.

ErbB3-Related Monospecific Antibody

AV-203 is a human immunoglobulin IgG1 antibody targeting ErbB3 that inhibits ligand-dependent and receptor-independent ErbB3 signaling. It has entered preclinical trials in the fields of breast cancer, head and neck cancer, lung cancer, ovarian cancer, and pancreatic cancer. There was no dose-limiting toxicity at the maximum dose of 20 mg/kg in the Phase I safety trial and entered the screening phase as a biomarker for potential patients.

LJM716 is a human anti-ErbB3 IgG1 antibody and is an antibody against the antigenic determinants of ErbB3 extracellular domain II and IV. ErbB3 is inhibited by an unactivated structure, preventing ligand-dependent and non-ligand-dependent ErbB3 activation. LJM716 can significantly inhibit the growth of different types of xenograft models. The growth of the mouse FaDu-loaded xenograft model in vivo was also significantly inhibited by LJM716. The success of LJM716 in animal experiments has laid a good foundation for conducting clinical trials.

ErbB3 and Breast Cancer

ErbB3 plays an important role in the development of normal breast tissue. The expression level of ErbB3 is very low in the normal breast tissue of the embryonic stage. ErbB3 expression is increased by postnatal maturation, and elevated levels of phosphorylation of ErbB3 are observed in the middle and late trimester of the rat. The expression of ErbB3 in the mammary ductal epithelium and mesenchyme of pregnant rats also increased. In functionally differentiated or non-transformed mammary epithelial cells, the expression and activation of ErbB3 is down-regulated or even absent. ErbB3 is also not activated in established normal immortal breast cell lines.

Approximately 35% of breast cancer cell lines express ErbB3 at high levels relative to non-transformed breast cell lines. In human breast cancer tissue samples, the expression of ErbB3 mRNA was increased by 100-fold in 46% of samples compared with normal breast tissue by Real-time PCR. Immunohistochemical methods ErbB3 protein is detected in 50%-70% of breast cancers. Moreover, in 18%-29% of cases, cancer tissues have higher ErbB3 expression than normal tissues. Highly expressed ErbB3 is positively associated with metastasis, tumor size and recurrence, tumor grade, and tumor recurrence. There are also studies suggesting that shortened survival is associated with overexpression of the ErbB3 protein.

In addition to monoclonal antibodies and small molecule tyrosine kinase inhibitors, other drugs with different mechanisms of action are being investigated, such as the negative regulation of ErbB3. It has been found that NRDP1 ubiquitinated ligase blocks the transactivation of ErbB3 and the transport of NRGs between the nucleus and the cytoplasm. In addition, siRNA that interferes with ErbB3 can also be used as a simple and effective means to highly inhibit the growth of lung xenografts in mice by simple intravenous injection of saline-dissolved siRNA.

ErbB3 is gaining more and more attention in the study of breast cancer. ErbB3 has extensive interactions with other ErbBs family members and estrogen and progesterone receptors, and each other's signal transduction pathways form a complex cross-communication network. This leads to the occurrence, recurrence and metastasis of breast cancer, and even affects the efficacy of chemotherapy and endocrine therapy in breast cancer. An in-depth study of ErbB3 will help us better understand the pathogenesis of breast cancer and design targeted molecularly targeted drugs.

References:

Ma, J., Lyu, H., Huang, J., & Liu, B. (2014). Targeting of erbb3 receptor to overcome resistance in cancer treatment. Molecular Cancer,13, 1(2014-05-08), 13(1), 105.
Hong, S. H., Lee, W. J., Kim, Y. D., Kim, H., Jeon, Y. J., & Lim, B., et al. (2016). Apip, an erbb3-binding partner, stimulates erbb2-3 heterodimer formation to promote tumorigenesis. Oncotarget, 7(16), 21601-21617.
Mujoo, K., Choi, B. K., Huang, Z., Zhang, N., & An, Z. (2014). Regulation of erbb3/her3 signaling in cancer. Oncotarget, 5(21), 10222-10236.
Lee, H., Lee, H., Chin, H., Kim, K., & Lee, D. (2014). Erbb3 knockdown induces cell cycle arrest and activation of bak and bax-dependent apoptosis in colon cancer cells. Oncotarget, 5(13), 5138-52.
Meetze, K., Vincent, S., Tyler, S., Mazsa, E. K., Delpero, A. R., & Bottega, S., et al. (2014). Neuregulin 1 expression is a predictive biomarker for response to av-203, an erbb3 inhibitory antibody, in human tumor models. European Journal of Cancer, 50(5), 120-120.

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