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There are four members in the HER family, HER1, HER2, HER3, and HER4. They are cytoplasmic membrane-anchored proteins with an extracellular ligand-binding domain, a transmembrane domain, and the intracellular tyrosine kinase domain. HER3 lacks RTK activity and relies on dimerization with HER2for phosphorylation.
Once phosphorylated, HER3 serves as a binding site for proteins that lead to downstream signaling pathways such as PI3K/AKT and more that regulate cell survival, proliferation, and apoptosis. The HER2/HER3 heterodimer is one of the main activators of the PI3K/AKT and Ras/MEK/ERK signaling pathways.
Downstream of these pathways are key regulations that would upregulate mesenchymal transition and lead to metastasis of breast cancer. HER2 does not directly to bind to any ligand but dimerizes with HER3 as previously mentioned as HER3 lacks RTK activity on its own. In cancer, HER2 homodimerize with itself when there is a high concentration. HER2 can localize to the nucleus and initiate transcriptional activity. Nuclear HER2 also acts as a STAT3 transcriptional co-activator. This stimulates breast cancer cell growth.
What are some cancer therapeutic drugs/treatments/strategies that target HER2 and HER3? How do they disrupt signaling pathway?
