HER2 Transgenic Mouse Models: A Way To HER2+ Breast Cancer Targeted Therapy
Breast cancer remains the second leading cause of cancer mortality in women worldwide despite major advances made in the recent years. About 20-30% of breast cancers cases show HER2 over expression and amplification which predicts poor prognosis. Though HER2 has been successfully targeted with anti-HER2 therapies including mAbs such as trastuzumab and tyrosine kinase inhibitors, resistance to trastuzumab is a major setback. Resistance is proposed to occur by steric hindrance of antibody binding to HER2, expression of mutant HER2 as well as increased PI3K/Akt pathway activation. Since there is need to develop better therapies, HER2 transgenic mouse models will contribute greatly to the search for these therepies.
The aim of this review is to analyse HER2 transgenic mouse models and demonstrate their potential towards development of new targeted therapy. The first model evaluated was generated in 2003 using wild-type HER2 and the whey acidic promoter (WAP) under the C57BL/6 background. The mouse was injected with ID8/E2, ovarian tumor cells and there was no tumor rejection in the transgenic mice which indicated tolerance to HER2. On vaccination with five cycles of a robust HER2 DNA based vaccine, there was induction of the immune system in the transgenic mice which was shown by anti-HER2 antibodies and 33% of the transgenic mice were protected from tumor growth. Consistent findings were obtained using the FVB-huHER2 mouse model which uses the MMTV promoter. In both models tolerance was broken by DNA vaccination hence offering protection.
A newer HER2+/PIK3CA mutant transgenic mouse using a Tet-inducible system for gene expression was described in 2013. It was shown that HER2+/PI3KCA expressing mice developed tumors with shorter latency compared to mice expressing HER2 or PI3KCA mutant oncogene alone. Cells from HER2+/PI3KCA tumors showed more lung metastases in the nude mice and the tumors were resistant to trastuzumab alone or in combination with lapatinib. Resistance was reversed by a PI3K inhibitor. This shows that increased PI3K activation has a role in trastuzumab resistance.
The transgenic mouse models expressing human wild-type HER2 oncogene only is suitable for testing of vaccines while the HER2+/PIK3CA mutant transgenic mouse model is suitable for studying trastuzumab resistance and testing of PI3K inhibitors. HER2 transgenic mouse models therefore have great potential towards development of better targeted therapy. If new drug targets are to be identified, new HER2 transgenic mouse models will need to be developed.
Key words: HER2, HER2 transgenic mouse, PI3K, targeted therapy, trastuzumab.
Marchini et al.HER2-Driven carcinogenesis: New mouse models for novel immunotherapies. Oncogene and Cancer-From Bench to Clinic 2013 Pages 41-66
De Giovanni et al: Vaccines against human HER2 prevent mammary carcinoma in mice transgenic for human HER2.Breast cancer Research 2014 16:R10.
Hanker et al. Mouse models and anti-HER2 therapies. Oncotarget 2013 Nov,Vol 4, No. 11
Diechocki et al .Human ErbB2 (HER2) transgenic mice: A model system for testing HER2 based vaccines. The Journal of Immunology 0022-1767/03
Masuda .H et al. Role of epidermal growth factor receptor in breast cancer. Breast cancer Res Treat (2012) 136: 331-345
Gottfried. E et al. Is there role of Epidermal Growth Factor Receptor Inhibitors in breast cancer prevention? Journal of the National Cancer Institute, Vol.95, No.24 Dec 17 2003.
Milani .A et al .Active Immunotherapy in HER2 over expressing breast cancer current status and future perspectives. Annals of oncology 00:1-9, 2013.
Hanker et al. Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to ant-HER2 therapies. Pg 14372-14377 PNAS August 27, 2013,Vol 110 No.35.