Abstract
HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.
Highlights
HER2 is a transmembrane tyrosine kinase belonging to the ERBB family of receptors (ERBB1-4)
After activation by death receptors, caspase 8 can cleave BH3-Interacting Domain Death Agonist (BID) to form truncated BID, which localizes to the mitochondria and activates Bax/Bak-dependent Mitochondrial Membrane Permeabilization (MOMP) leading to apoptosis
AKT-mediated down regulation of FOXO family members leads to increased survivin expression [16] and survivin expression can be increased by AKT-mediated activation of NF-κB [31,32]. These results clearly show HER2 expression promotes survivin expression leads to decreased apoptosis
Summary
HER2 (or ERBB2/Neu) is a transmembrane tyrosine kinase belonging to the ERBB family of receptors (ERBB1-4). ERBB receptors hetero and homo-dimerize resulting in activation of tyrosine kinase activity. ERBB tyrosine receptor kinases activate several pathways, including PI3K-AKT and RAS-MAPK pathways, which regulate many cell functions including proliferation, migration, survival, and cell growth among others. Hyperactivation or overexpression of these receptors can lead to uncontrolled cell growth and proliferation leading to cancer development. HER2, is overexpressed in 2030% of breast cancers and this overexpression is associated with poor patient outcomes [1,2,3]. One of the hallmarks of cancer is the resistance to apoptosis [4,5] and HER2 overexpression leads to suppression of apoptosis. This review will focus on the known mechanisms by which HER2 suppresses apoptosis in breast cancer cells
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