One-third of patients with breast cancer overexpress the ERBB2 receptor tyrosine kinase, which is associated not only with a more aggressive phenotype but also reduced responsiveness to hormonal therapies. Over the past two decades, many ERBB2 mouse models for breast cancer have conclusively shown that this receptor has a causal role in breast cancer development. These mouse models have also enabled the mechanisms controlling tumour growth, angiogenesis, metastasis, dormancy and recurrence in ERBB2-positive breast cancer to be elucidated. In addition, a mouse model has recently been described that accurately recapitulates many of the hallmarks associated with the early stages of the human disease.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Shih, C., Padhy, L. C., Murray, M. & Weinberg, R. A. Transforming genes of carcinomas and neuroblastomas introduced into mouse fibroblasts. Nature 290, 261–264 (1981).
Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185, 000-Mr tumour antigen. Nature 312, 513–516 (1984).
Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).
Muller, W. J., Sinn, E., Pattengale, P. K., Wallace, R. & Leder, P. Single-step induction of mammary adenocarcinoma in transgenic mice bearing the activated c-neu oncogene. Cell 54, 105–115 (1988).
Bouchard, L., Lamarre, L., Tremblay, P. J. & Jolicoeur, P. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c-neu oncogene. Cell 57, 931–6 (1989).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).
Romond, E. H. et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N. Engl. J. Med. 353, 1673–1684 (2005).
Piccart-Gebhart, M. J. et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353, 1659–1672 (2005).
Robert, N. et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J. Clin. Oncol. 24, 2786–2792 (2006).
Stewart, T. A., Pattengale, P. K. & Leder, P. Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38, 627–637 (1984).
Sinn, E. et al. Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49, 465–475 (1987).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Activated neu induces rapid tumor progression. J. Biol. Chem. 271, 7673–7678 (1996).
Lemoine, N. R., Staddon, S., Dickson, C., Barnes, D. M. & Gullick, W. J. Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene 5, 237–239 (1990).
Guy, C. T. et al. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc. Natl Acad. Sci. USA 89, 10578–10582 (1992).
Siegel, P. M., Dankort, D. L., Hardy, W. R. & Muller, W. J. Novel activating mutations in the neu proto-oncogene involved in induction of mammary tumors. Mol. Cell. Biol. 14, 7068–7077 (1994).
Siegel, P. M. & Muller, W. J. Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc. Natl Acad. Sci. USA 93, 8878–8883 (1996).
Siegel, P. M., Ryan, E. D., Cardiff, R. D. & Muller, W. J. Elevated expression of activated forms of Neu/ErbB-2 and ErbB-3 are involved in the induction of mammary tumors in transgenic mice: implications for human breast cancer. EMBO J. 18, 2149–2164 (1999).
Chan, R., Muller, W. J. & Siegel, P. M. Oncogenic activating mutations in the neu/erbB-2 oncogene are involved in the induction of mammary tumors. Ann. NY Acad. Sci. 889, 45–51 (1999).
Kwong, K. Y. & Hung, M. C. A novel splice variant of HER2 with increased transformation activity. Mol. Carcinog. 23, 62–68 (1998).
Garrett, T. P. et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell 11, 495–505 (2003).
Naidu, R., Yadav, M., Nair, S. & Kutty, M. K. Expression of c-erbB3 protein in primary breast carcinomas. Br. J. Cancer 78, 1385–1390 (1998).
Dankort, D. L., Wang, Z., Blackmore, V., Moran, M. F. & Muller, W. J. Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol. Cell. Biol. 17, 5410–5425 (1997).
Dankort, D., Jeyabalan, N., Jones, N., Dumont, D. J. & Muller, W. J. Multiple ErbB-2/Neu phosphorylation sites mediate transformation through distinct effector proteins. J. Biol. Chem. 276, 38921–38928 (2001).
Dankort, D. et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol. Cell. Biol. 21, 1540–1551 (2001).
Moody, S. E. et al. Conditional activation of Neu in the mammary epithelium of transgenic mice results in reversible pulmonary metastasis. Cancer Cell 2, 451–461 (2002).
Moody, S. E. et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8, 197–209 (2005).
Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).
de Candia, P. et al. Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors. Proc. Natl Acad. Sci. USA 100, 12337–12342 (2003).
Howe, L. R. et al. HER2/neu-induced mammary tumorigenesis and angiogenesis are reduced in cyclooxygenase-2 knockout mice. Cancer Res. 65, 10113–10119 (2005).
Oshima, R. G. et al. Angiogenic acceleration of Neu induced mammary tumor progression and metastasis. Cancer Res. 64, 169–79 (2004).
Rodriguez-Manzaneque, J. C. et al. Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 98, 12485–12490 (2001).
Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J. & Massague, J. Transforming growth factor b signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl Acad. Sci. USA 100, 8430–8435 (2003).
Muraoka, R. S. et al. Increased malignancy of Neu-induced mammary tumors overexpressing active transforming growth factor β1. Mol. Cell. Biol. 23, 8691–8703 (2003).
Muraoka-Cook, R. S. et al. Activated type I TGFβ receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25, 3408–3423 (2006).
Hutchinson, J. N., Jin, J., Cardiff, R. D., Woodgett, J. R. & Muller, W. J. Activation of Akt-1 (PKB-α) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res. 64, 3171–3178 (2004).
Yoeli-Lerner, M. et al. Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol. Cell 20, 539–550 (2005).
Guo, W. et al. Beta 4 integrin amplifies ErbB2 signaling to promote mammary tumorigenesis. Cell 126, 489–502 (2006).
Julien, S. G. et al. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nature Genet. 39, 338–346 (2007).
Reddy, H. K. et al. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 65, 10174–10178 (2005).
Landis, M. W., Pawlyk, B. S., Li, T., Sicinski, P. & Hinds, P. W. Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 9, 13–22 (2006).
Bowe, D. B., Kenney, N. J., Adereth, Y. & Maroulakou, I. G. Suppression of Neu-induced mammary tumor growth in cyclin D1 deficient mice is compensated for by cyclin E. Oncogene 21, 291–298 (2002).
Bulavin, D. V. et al. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nature Genet. 36, 343–350 (2004).
Wulf, G., Garg, P., Liou, Y. C., Iglehart, D. & Lu, K. P. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J. 23, 3397–3407 (2004).
Li, B., Rosen, J. M., McMenamin-Balano, J., Muller, W. J. & Perkins, A. S. neu/ERBB2 cooperates with p53–172H during mammary tumorigenesis in transgenic mice. Mol. Cell. Biol. 17, 3155–3163 (1997).
Hulit, J. et al. p27Kip1 repression of ErbB2-induced mammary tumor growth in transgenic mice involves Skp2 and Wnt/β-catenin signaling. Cancer Res. 66, 8529–8541 (2006).
Cabodi, S. et al. p130Cas as a new regulator of mammary epithelial cell proliferation, survival, and HER2-neu oncogene-dependent breast tumorigenesis. Cancer Res. 66, 4672–4680 (2006).
Katsumata, M. et al. Prevention of breast tumour development in vivo by downregulation of the p185neu receptor. Nature Med. 1, 644–648 (1995).
Dakappagari, N. K., Douglas, D. B., Triozzi, P. L., Stevens, V. C. & Kaumaya, P. T. Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine. Cancer Res. 60, 3782–3789 (2000).
Sakai, Y. et al. Vaccination by genetically modified dendritic cells expressing a truncated neu oncogene prevents development of breast cancer in transgenic mice. Cancer Res. 64, 8022–8028 (2004).
Holmgren, L. et al. A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth. Proc. Natl Acad. Sci. USA 103, 9208–9213 (2006).
Howe, L. R. et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 62, 5405–5407 (2002).
Dang, C. T. et al. Phase II study of celecoxib and trastuzumab in metastatic breast cancer patients who have progressed after prior trastuzumab-based treatments. Clin. Cancer Res. 10, 4062–4067 (2004).
Canney, P. A., Machin, M. A. & Curto, J. A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer. Eur. J. Cancer 42, 2751–2756 (2006).
Liu, M. et al. Antitumor activity of rapamycin in a transgenic mouse model of ErbB2-dependent human breast cancer. Cancer Res. 65, 5325–5336 (2005).
Andrechek, E. R. et al. Amplification of the neu/erbB-2 oncogene in a mouse model of mammary tumorigenesis. Proc. Natl Acad. Sci. USA 97, 3444–3449 (2000).
Montagna, C., Andrechek, E. R., Padilla-Nash, H., Muller, W. J. & Ried, T. Centrosome abnormalities, recurring deletions of chromosome 4, and genomic amplification of HER2/neu define mouse mammary gland adenocarcinomas induced by mutant HER2/neu. Oncogene 21, 890–898 (2002).
Hodgson, J. G. et al. Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res. 65, 9695–9704 (2005).
Kauraniemi, P., Kuukasjarvi, T., Sauter, G. & Kallioniemi, A. Amplification of a 280-kilobase core region at the ERBB2 locus leads to activation of two hypothetical proteins in breast cancer. Am. J. Pathol. 163, 1979–1984 (2003).
Stein, D. et al. The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer. EMBO J. 13, 1331–1340 (1994).
Mano, M. S., Rosa, D. D., De Azambuja, E., Ismael, G. F. & Durbecq, V. The 17q12-q21 amplicon: Her2 and topoisomerase-IIa and their importance to the biology of solid tumours. Cancer Treat. Rev. 33, 64–77 (2007).
Muss, H. B. et al. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N. Engl. J. Med. 330, 1260–1266 (1994).
Pritchard, K. I. et al. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N. Engl. J. Med. 354, 2103–2111 (2006).
Kingsmore, S. F. et al. Genetic mapping of the mouse topoisomerase II α gene to chromosome 11. Mamm. Genome 4, 288–289 (1993).
Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).
Radany, E. H., Hong, K., Kesharvarzi, S., Lander, E. S. & Bishop, J. M. Mouse mammary tumor virus/v-Ha-ras transgene-induced mammary tumors exhibit strain-specific allelic loss on mouse chromosome 4. Proc. Natl Acad. Sci. USA 94, 8664–8669 (1997).
Weaver, Z. A. et al. A recurring pattern of chromosomal aberrations in mammary gland tumors of MMTV-cmyc transgenic mice. Genes Chromosomes Cancer 25, 251–260 (1999).
Hermeking, H. The 14–3-3 cancer connection. Nature Rev. Cancer 3, 931–943 (2003).
Gunther, K. et al. Differences in genetic alterations between primary lobular and ductal breast cancers detected by comparative genomic hybridization. J. Pathol. 193, 40–47 (2001).
Borg, A., Zhang, Q. X., Olsson, H. & Wenngren, E. Chromosome 1 alterations in breast cancer: allelic loss on 1p and 1q is related to lymphogenic metastases and poor prognosis. Genes Chromosomes Cancer 5, 311–320 (1992).
Bieche, I., Champeme, M. H. & Lidereau, R. A tumor suppressor gene on chromosome 1p32-pter controls the amplification of MYC family genes in breast cancer. Cancer Res. 54, 4274–4276 (1994).
Ferguson, A. T. et al. High frequency of hypermethylation at the 14–3-3 sigma locus leads to gene silencing in breast cancer. Proc. Natl Acad. Sci. USA 97, 6049–6054 (2000).
Umbricht, C. B. et al. Hypermethylation of 14–3-3 sigma (stratifin) is an early event in breast cancer. Oncogene 20, 3348–3353 (2001).
Vercoutter-Edouart, A. S. et al. Proteomic analysis reveals that 14–3-3sigma is down-regulated in human breast cancer cells. Cancer Res. 61, 76–80 (2001).
Andrechek, E. R. et al. Gene expression profiling of neu-induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2-expressing human breast cancers. Cancer Res. 63, 4920–4926 (2003).
Cardiff, R. D. & Wellings, S. R. The comparative pathology of human and mouse mammary glands. J. Mammary Gland. Biol. Neoplasia 4, 105–122 (1999).
Rosner, A. et al. Pathway pathology: histological differences between ErbB/Ras and Wnt pathway transgenic mammary tumors. Am. J. Pathol. 161, 1087–1097 (2002).
Dontu, G., Liu, S. & Wicha, M. S. Stem cells in mammary development and carcinogenesis: implications for prevention and treatment. Stem Cell Rev. 1, 207–214 (2005).
Wicha, M. S., Liu, S. & Dontu, G. Cancer stem cells: an old idea-a paradigm shift. Cancer Res. 66, 1883–1890 (2006).
Li, Y. et al. Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl Acad. Sci. USA 100, 15853–15858 (2003).
Shackleton, M. et al. Generation of a functional mammary gland from a single stem cell. Nature 439, 84–88 (2006).
Hortobagyi, G. N. Overview of treatment results with trastuzumab (Herceptin) in metastatic breast cancer. Semin. Oncol. 28, 43–47 (2001).
Pegram, M. & Ngo, D. Application and potential limitations of animal models utilized in the development of trastuzumab (Herceptin): a case study. Adv. Drug Deliv. Rev. 58, 723–734 (2006).
Stocklin, E., Botteri, F. & Groner, B. An activated allele of the c-erbB-2 oncogene impairs kidney and lung function and causes early death of transgenic mice. J. Cell Biol. 122, 199–208 (1993).
Piechocki, M. P., Ho, Y. S., Pilon, S. & Wei, W. Z. Human ErbB-2 (Her-2) transgenic mice: a model system for testing Her-2 based vaccines. J. Immunol. 171, 5787–5794 (2003).
Finkle, D. et al. HER2-targeted therapy reduces incidence and progression of midlife mammary tumors in female murine mammary tumor virus huHER2-transgenic mice. Clin. Cancer Res. 10, 2499–2511 (2004).
Cardiff, R. D. & Muller, W. J. Transgenic mouse models of mammary tumorigenesis. Cancer Surv. 16, 97–113 (1993).
Wagner, K. U. et al. Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res. 10, 545–553 (2001).
Otten, A. D., Sanders, M. M. & McKnight, G. S. The MMTV LTR promoter is induced by progesterone and dihydrotestosterone but not by estrogen. Mol. Endocrinol. 2, 143–147 (1988).
We gratefully acknowledge the following funding agencies for their support: Department of Defense Breast Cancer Research Centers of Excellence (DOD), Canadian Institute of Health Research (CIHR), National Cancer Institute of Canada (NCIC-Terry Fox Group Grant), The Cancer Research Society (CRS), Canadian Breast Cancer Research Alliance (CBCRA) and US National Institutes of Health (NIH).
The authors declare no competing financial interests.
About this article
Cite this article
Ursini-Siegel, J., Schade, B., Cardiff, R. et al. Insights from transgenic mouse models of ERBB2-induced breast cancer. Nat Rev Cancer 7, 389–397 (2007). https://doi.org/10.1038/nrc2127
Rheb1-Independent Activation of mTORC1 in Mammary Tumors Occurs through Activating Mutations in mTOR
Cell Reports (2020)
Cell Cycle (2020)
Breast Cancer Research and Treatment (2020)
Cytokine & Growth Factor Reviews (2020)
International Journal of Molecular Sciences (2019)