Table 1. Use of transgenic mouse models engaging HER2/neu in clinical applications.

Gene-engineered mice that overexpress HER2/neu (wild type or mutant) in mammary glands, and their clinical uses are summarized. The MMTV promoter has been used in all the cases except for WAP-HER2 (ref. 135), which did not produce spontaneous mammary tumors, but were tolerant for HER2. The MMTV-NIC is a unique model that expresses neuNT and cre recombinase simultaneously to study the collaboration between oncogenic new expression and oncogene/tumor suppressor gene inactivation. These mice have been used in characterization of tumor initiating cells (TIC), testing the HSP90 inhibitor tanespimycin (17-AAG), anti-tumor cytokines (IL-12, IL-24), HER2 vaccines (DNA, peptide), HER(2) kinase inhibitors (lapanitib, erlotinib, and others), PI3K inhibitors, and monoclonal antibodies (trastuzumab, pertuzumab).

Mouse model	Mean latency of tumors	Pathology	Clinical Use	References
MMTV-neuNT (mutant), FVB or Balb/c	197 days	Rapidly growing, invasive mammary tumors, metastatic*	17-AAG, MoAb, Vac	29; 100; 105; 139, 149
MMTV-neuNT (mutant), Balb/c	21 weeks	Rapidly growing, multifocal mammary tumors*	Cytokine therapy; Vac	122; 123–126; 135–138, 140
MMTV-neu (wild type)	205 - 367 days	Focal Adca, lung metastasis after long latency	TIC, Cytokine therapy, TKI Vac, TKI	30; 67; 84–88; 90, 123, 124; 130
MMTV-NIC (neu-IRES-Cre)	146 days	Aggressive mammary tumors		91, 95
MMTV-NIC;Ptenflox/flox	43 vs. 198 days		PI3KI	96
MMTV-NIC;p110αflox/flox	95% survival at 225 days		PI3KI	106
MMTV-NIC;p110βflox/flox	125 vs. 135 days			106
MMTV-HER2*	28 weeks	Adca with areas of solid, tubular, and papillary growth cellular polymorphism with mitosis and metastasis	MoAb	35
MMTV-HER2*; MMTV-rtTA; TetOp-HA-PIKCAH1047R	76 days	Rapidly growing, large, multiple tumors; increased angiogenesis, lung metastasis; EMT; mammospheres	MoAb, PI3KI	97
MMTV-HER2*Δ16	17 weeks	Tubular adca consisting of outer pale cells, an intermediate darker fusiform cells, and an inner zcells with pinkish cytoplasm	MoAb	37
WAP-HER2*	no tumor	None of the tissues expressing HER2 demonstrated obvious abnormality The mice were healthy and have a normal life span.	Vac	135
	neuNT: mutant rat neu MMTV-NIC; bicistronic vector expressing rat neu and cre recombinase HER2*: wild type human ErbB2	Adca: Adenocarcinoma *independent of pregnancy	TKI: tyrosine kinase inhibitor screening Vac: vaccine development TIC: tumor initiating cells MoAb: monoclonal antibody screening