Clinical applications of mouse models for breast cancer engaging HER2/neu

The genomic locus for HER2 is amplified in ~20 % and the protein is overexpressed in ~30 % of human BCs, and is associated with aggressive disease with shorter overall and disease-free survival []. EGFR (HER1) is activated by growth factor-ligands such as epidermal growth factor (EGF), heparin binding EGF (HB-EGF), amphiregulin (Areg), transforming growth factor alpha (TGF-α), betacellulin, epiregulin, and epigen [–, , ]. Heregulins/neuregulins (HRGs/NRGs) are the ligands for HER3 and HER4 []. Currently there are four known NRG genes: NRG1, NHRG2, NRG3 and NRG4 [, ]. Following ligand engagement, HER1-4 engages and allosterically activates its kinase partner, in this case HER2. Although HER2 molecules make both homo-and hetero-dimers, HER3 do not form homodimers, and does not have protein-tyrosine kinase activity. Phosphorylation of its C-terminal tail leads to recruitment of adapter proteins leading to activation of Pi3k and Ras pathways [–, ]. Activation of Pi3k leads to phosphorylation of membrane phosphoinositides producing PIP3, which in turn docks the PH domain-containing proteins Pdk1 and Akt []. Membrane - bound Akt is phosphorylated and activated by Pdk1. Activated Akt proceeds to phosphorylate a plethora of cellular substrates involved in diverse biological processes. These processes include accelerated G1-S progression as demonstrated by increased cyclin D1 and decreased p27Kip1 levels, and enhanced cell survival through increased phosphorylation of Bad and increased NF-κB levels [–, ]. Indeed aberrant overexpression of cyclin D1 is frequently observed in human cancers, caused by different mechanisms []. Thus deregulation of HER2 leads to tumorigenesis. Aberrant overexpression of HER2 activates the Dmp1 promoter to stimulate the Arf-Mdm2-p53 self-autonomous tumor surveillance pathway through Pi3k-Akt-NF-κB and Ras-Raf-Mek-Erk-Jun cascades to eliminate incipient cancer cells by cell cycle arrest or apoptosis [, , , ].Trastuzumab (Herceptin®) binds the extracellular domain of HER2. Pertuzumab (Perjeta®) binds another HER2 domain, preventing dimerization. Tanespimycin (17-AAG) inhibits HSP90, causing HER2 conformation change. Lapatinib is a small-molecule tyrosine kinase that inhibits HER1 and HER2. Erlotinib is a specific inhibitor for HER1. AZD8931 is a pan-HER family tyrosine-kinase inhibitor.

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Clinical applications of mouse models for breast cancer engaging HER2/neu. () Elizabeth A. Fry, et al. Integr Cancer Sci Ther. ;3(5):593-603. Figure: F1. All organisms Mus musculus Homo sapiens Rattus norvegicus Bos taurus Danio rerio

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