For example, ErbB-2 and ErbB-4 knockout mice die at midgestation leads to deficient cardiac function associated with a lack of myocardial ventricular trabeculation and display abnormal development of the peripheral nervous system.
[2] The ErbB protein family consists of 4 members v-ErbBs are homologous to EGFR, but lack sequences within the ligand binding ectodomain.
[4][9] The figure below shows the tridimensional structure of the ErbB family proteins, using the pdb files 1NQL (ErbB-1), 1S78 (ErbB-2), 1M6B (ErbB-3) and 2AHX (ErbB-4):[10][11][12][13] The four members of the ErbB protein family are capable of forming homodimers, heterodimers, and possibly higher-order oligomers upon activation by a subset of potential growth factor ligands.
[18] Notably, the ErbB1 and ErbB4 are the two most studied and intact among the family of ErbB proteins, Which forms functional intracellular tyrosine kinases.
[17][18] When not bound to a ligand, the extracellular regions of ErbB1, ErbB3, and ErbB4 are found in a tethered conformation in which a 10-amino-acid-long dimerization arm is unable to mediate monomer-monomer interactions.
In contrast, in ligand-bound ErbB-1 and unliganded ErbB-2, the dimerization arm becomes untethered and exposed at the receptor surface, making monomer-monomer interactions and dimerisation possible.
At least 10 specific tyrosines, 7 serines, and 2 threonines have been identified within the cytoplasmic domain of ErbB-1, that may become phosphorylated and in some cases de-phosphorylated (e.g., Tyr 992) upon receptor dimerization.
[27] Many breast tumors also have lower levels of PTEN, which is a lipid phosphatase that dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate, thereby reversing the action of PI3K.
[28] ErbB2 overexpression can occur in breast, ovarian, bladder, non-small-cell lung carcinoma, as well as several other tumor types.
[28] Trastuzumab targets tumor cells and causes apoptosis through the immune system by promoting antibody-dependent cellular cytotoxicity.
Research suggests that a low FISH test ratio in estrogen receptor positive breast cancers are less likely to respond to this drug.