Key Points
-
Identifying effective cancer chemopreventive agents will significantly reduce cancer morbidity and mortality, especially in high-risk individuals.
-
Genetically engineered mouse (GEM) models of cancer must be assessed carefully for their relevance to human disease and for their predictive power for determining a cancer-prevention response in humans.
-
Relatively fast and inexpensive testing of selected compounds can be performed using appropriate mouse models.
-
Stage-specific responses to chemopreventive agents can be determined using GEM models, unlike TUMOUR XENOGRAFT models.
-
Combination therapies targeting multiple oncogenic pathways can be performed readily in mouse models.
-
GEM colon cancer models can be used to study the effects of chemopreventive agents on tumours arising from genetic lesions that are associated with multi-step carcinogenesis.
-
Mammary cancer mouse models have demonstrated that certain preventive agents might prevent the transition from pre-invasive to invasive carcinoma.
-
Nutritional supplements that target different molecular pathways are effective in a prostate cancer model.
-
The ultimate goal remains the establishment of improved models that can be used for the predictive testing of preventive responses in humans.
Abstract
Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features of human oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems for determining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemoprevention will help the selection of appropriate agents for large-scale clinical trials and allow the testing of combination therapies.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998). Major study demonstrating that the anti-oestrogen tamoxifen could significantly reduce the incidence of oestrogen receptor-positive breast cancer in women at increased risk.
Sporn, M. B. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res. 36, 2699–2702 (1976). First published report to indicate that chemoprevention approaches might reduce cancer incidence.
Dannenberg, A. J. & Zakim, D. Chemoprevention of colorectal cancer through inhibition of cyclooxygenase-2. Semin. Oncol. 26, 499–504 (1999).
Klein, E. A. et al. SELECT: the selenium and vitamin E cancer prevention trial. Urol. Oncol. 21, 59–65 (2003). Description of a large, ongoing, long-term, prospective human trial to assess whether selenium or vitamin E can prevent prostate cancer. This demonstrates the logistical and expensive nature of such types of human clinical trials.
Cardiff, R. D. et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene 19, 968–988 (2000). First major study to report a consensus between human and veterinary pathologists in describing the mammary cancer pathology of genetically engineered mice with human breast cancer pathology.
Shappell, S. B. et al. Prostate pathology of genetically engineered mice: definitions and classification. The consensus report from the Bar Harbor meeting of the Mouse Models of Human Cancer Consortium Prostate Pathology Committee. Cancer Res. 64, 2270–2305 (2004).
Boivin, G. P. et al. Pathology of mouse models of intestinal cancer: consensus report and recommendations. Gastroenterology 124, 762–777 (2003).
Weaver, Z. et al. Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer. Oncogene 21, 5097–5107 (2002).
Desai, K. V. et al. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc. Natl Acad. Sci. USA 99, 6967–6972 (2002). First study to demonstrate that gene-expression signatures can distinguish mouse mammary cancers from several transgenic models based on the initiating genetic alteration.
Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003).
Hunter, K., Welch, D. R. & Liu, E. T. Genetic background is an important determinant of metastatic potential. Nature Genet. 34, 23–24; author reply 25 (2003). Provocative finding that gene expression changes that are correlated with a high incidence mouse mammary cancer metastases based on the genetic background follow a similar pattern as a gene expression signature for human metastases.
Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).
van 't Veer, L. J. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530–536 (2002).
van de Vijver, M. J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).
Balmain, A. & Nagase, H. Cancer resistance genes in mice: models for the study of tumour modifiers. Trends Genet. 14, 139–144 (1998).
Dragani, T. A. 10 years of mouse cancer modifier loci: human relevance. Cancer Res. 63, 3011–3018 (2003).
Naumov, G. N. et al. Persistence of solitary mammary carcinoma cells in a secondary site: a possible contributor to dormancy. Cancer Res. 62, 2162–2168 (2002).
Riethmuller, G. & Klein, C. A. Early cancer cell dissemination and late metastatic relapse: clinical reflections and biological approaches to the dormancy problem in patients. Semin. Cancer Biol. 11, 307–311 (2001).
Green, J. E. et al. 2-difluoromethylornithine and dehydroepiandrosterone inhibit mammary tumor progression but not mammary or prostate tumor initiation in C3(1)/SV40 T/t-antigen transgenic mice. Cancer Res. 61, 7449–7455 (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).
Tang, X. et al. Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/− mice. J. Clin. Invest. 113, 867–875 (2004).
Demierre, M. -F. & Merlino, G. Chemoprevention of Melanoma. Curr. Oncol. Rep. 6, 406–413 (2004).
Lubet, R. A., Zhang, Z., Wang, Y. & You, M. Chemoprevention of lung cancer in transgenic mice. Chest 125, 144S–147S (2004).
Jin, L. et al. Indole-3-carbinol prevents cervical cancer in human papilloma virus type 16 (HPV16) transgenic mice. Cancer Res. 59, 3991–3997 (1999).
Padua, R. A. et al. PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia. Nature Med. 9, 1413–1417 (2003).
Torrance, C. J. et al. Combinatorial chemoprevention of intestinal neoplasia. Nature Med. 6, 1024–1028 (2000).
Moser, A. R., Pitot, H. C. & Dove, W. F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990).
Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).
Nelson, W. J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).
Oshima, M. et al. Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc. Natl Acad. Sci. USA 92, 4482–4486 (1995).
Smits, R. et al. Loss of Apc and the entire chromosome 18 but absence of mutations at the Ras and Tp53 genes in intestinal tumors from Apc1638N, a mouse model for Apc-driven carcinogenesis. Carcinogenesis 18, 321–327 (1997).
Harada, N. et al. Intestinal polyposis in mice with a dominant stable mutation of the β-catenin gene. EMBO J. 18, 5931–5942 (1999).
Iinuma, T. et al. Prevention of gastrointestinal tumors based on adenomatous polyposis coli gene mutation by dendritic cell vaccine. J. Clin. Invest. 113, 1307–1317 (2004).
Patel, A. C., Nunez, N. P., Perkins, S. N., Barrett, J. C. & Hursting, S. D. Effects of energy balance on cancer in genetically altered mice. J. Nutr. 134, 3394S–3398S (2004).
Mai, V. et al. Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in ApcMin mice through different mechanisms. Cancer Res. 63, 1752–1755 (2003).
Colbert, L. H. et al. Exercise and intestinal polyp development in APCMin mice. Med. Sci. Sports Exerc. 35, 1662–1669 (2003).
Russo, M. W., Murray, S. C., Wurzelmann, J. I., Woosley, J. T. & Sandler, R. S. Plasma selenium levels and the risk of colorectal adenomas. Nutr. Cancer 28, 125–129 (1997).
Rao, C. V. et al. Chemoprevention of familial adenomatous polyposis development in the Apcmin mouse model by 1, 4-phenylene bis (methylene) selenocynate. Carcinogenesis 21, 617–621 (2000).
Gupta, R. A. & DuBois, R. N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Rev. Cancer 1, 11–21 (2001). Excellent review of colon cancer prevention through the inhibition of cyclooxygenase-2.
Oshima, M. et al. Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).
Beazer-Barclay, Y. et al. Sulindac suppresses tumorigenesis in the Min mouse. Carcinogenesis 17, 1757–1760 (1996).
Sansom, O. J., Stark, L. A., Dunlop, M. G. & Clarke, A. R. Suppression of intestinal and mammary neoplasia by lifetime administration of aspirin in ApcMin/+ and ApcMin/+, Msh2−/− mice. Cancer Res. 61, 7060–7064 (2001).
MacGregor, D. J., Kim, Y. S., Sleisenger, M. H. & Johnson, L. K. Chemoprevention of colon cancer carcinogenesis by balsalazide: inhibition of azoxymethane-induced aberrant crypt formation in the rat colon and intestinal tumor formation in the B6-Min/+ mouse. Int. J. Oncol. 17, 173–179 (2000).
Jacoby, R. F., Seibert, K., Cole, C. E., Kelloff, G. & Lubet, R. A. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 60, 5040–5044 (2000).
Corpet, D. E. & Pierre, F. Point: From animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol. Biomarkers Prev. 12, 391–400 (2003). This paper shows that the effects of preventive agents on gastrointestinal tumorigenesis in the rat axomethane (AOM) model and the mouse Apcmin/+ model correlate well with clinical data indicating that these models might be able to predict the response of preventive agents in humans.
Kitamura, T. et al. Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis. Carcinogenesis 23, 1463–1466 (2002).
Wechter, W. J. et al. R-flurbiprofen chemoprevention and treatment of intestinal adenomas in the APCMin/+ mouse model: implications for prophylaxis and treatment of colon cancer. Cancer Res. 57, 4316–4324 (1997).
Kennedy, A. R., Beazer-Barclay, Y., Kinzler, K. W. & Newberne, P. M. Suppression of carcinogenesis in the intestines of min mice by the soybean-derived Bowman-Birk inhibitor. Cancer Res. 56, 679–682 (1996).
Paulsen, J. E., Elvsaas, I. K., Steffensen, I. L. & Alexander, J. A fish oil derived concentrate enriched in eicosapentaenoic and docosahexaenoic acid as ethyl ester suppresses the formation and growth of intestinal polyps in the Min mouse. Carcinogenesis 18, 1905–1910 (1997).
Petrik, M. B., McEntee, M. F., Johnson, B. T., Obukowicz, M. G. & Whelan, J. Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in ApcMin/+ mice. J. Nutr. 130, 2434–2443 (2000).
Schneider, Y. et al. Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. Nutr. Cancer 39, 102–107 (2001).
Song, J., Medline, A., Mason, J. B., Gallinger, S. & Kim, Y. I. Effects of dietary folate on intestinal tumorigenesis in the ApcMin mouse. Cancer Res. 60, 5434–5440 (2000).
Lamprecht, S. A. & Lipkin, M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nature Rev. Cancer 3, 601–614 (2003).
Mahmoud, N. N. et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis 21, 921–927 (2000).
Erdman, S. H. et al. APC-dependent changes in expression of genes influencing polyamine metabolism, and consequences for gastrointestinal carcinogenesis, in the Min mouse. Carcinogenesis 20, 1709–1713 (1999).
Perkins, S. et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the Min/+ mouse, a model of familial adenomatous polyposis. Cancer Epidemiol. Biomarkers Prev. 11, 535–540 (2002).
Orner, G. A. et al. Response of Apcmin and A33 (Δ N β-cat) mutant mice to treatment with tea, sulindac, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Mutat. Res. 506-507, 121–127 (2002).
Jacoby, R. F. et al. Chemopreventive efficacy of combined piroxicam and difluoromethylornithine treatment of Apc mutant Min mouse adenomas, and selective toxicity against Apc mutant embryos. Cancer Res. 60, 1864–1870 (2000).
Reitmair, A. H. et al. Spontaneous intestinal carcinomas and skin neoplasms in Msh2-deficient mice. Cancer Res. 56, 3842–3849 (1996).
Kuraguchi, M. et al. The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis. Cancer Res. 61, 7934–7942 (2001).
Shoemaker, A. R. et al. Mlh1 deficiency enhances several phenotypes of ApcMin/+ mice. Oncogene 19, 2774–2779 (2000).
Zhu, Y., Richardson, J. A., Parada, L. F. & Graff, J. M. Smad3 mutant mice develop metastatic colorectal cancer. Cell 94, 703–714 (1998).
Takaku, K. et al. Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92, 645–656 (1998).
Engle, S. J. et al. Elimination of colon cancer in germ-free transforming growth factor β 1-deficient mice. Cancer Res. 62, 6362–6366 (2002).
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).
Jordan, V. C. Chemosuppression of breast cancer with tamoxifen: laboratory evidence and future clinical investigations. Cancer Invest. 6, 589–595 (1988).
Brodie, A. M., Schwarzel, W. C., Shaikh, A. A. & Brodie, H. J. The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer. Endocrinology 100, 1684–1695 (1977).
Yoshidome, K., Shibata, M. -A., Couldrey, C., Korach, K. S. & Green, J. E. Estrogen promotes increased mammary tumor development in C3(1)/SV40 Tag transgenic mice: paradoxical loss of ERα expression during tumor development. Cancer Res. 60, 6901–6910 (2000).
Menard, S. et al. Tamoxifen chemoprevention of a hormone-independent tumor in the proto-neu transgenic mice model. Cancer Res. 60, 273–275 (2000).
Medina, D. et al. Hormone dependence in premalignant mammary progression. Cancer Res. 63, 1067–1072 (2003).
Lin, S. C. et al. Somatic mutation of p53 leads to estrogen receptor α-positive and -negative mouse mammary tumors with high frequency of metastasis. Cancer Res. 64, 3525–3532 (2004).
Kelsey, J. L. & Gammon, M. D. The epidemiology of breast cancer. CA Cancer. J. Clin. 41, 146–165 (1991).
Medina, D. Breast cancer: the protective effect of pregnancy. Clin. Cancer Res. 10, 380S–384S (2004).
Russo, I. H. & Russo, J. Hormonal approach to breast cancer prevention. J. Cell Biochem. Suppl. 34, 1–6 (2000).
Wu, K. et al. Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol. Biomarkers Prev. 11, 467–474 (2002).
Rao, G. N., Ney, E. & Herbert, R. A. Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene. Breast Cancer Res. Treat. 58, 241–254 (1999).
Chen, Y., Hu, D., Eling, D. J., Robbins, J. & Kipps, T. J. DNA vaccines encoding full-length or truncated Neu induce protective immunity against Neu-expressing mammary tumors. Cancer Res. 58, 1965–1971 (1998).
Nanni, P. et al. Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J. Exp. Med. 194, 1195–1205 (2001).
Rovero, S. et al. Insertion of the DNA for the 163-171 peptide of IL1β enables a DNA vaccine encoding p185neu to inhibit mammary carcinogenesis in Her-2/neu transgenic BALB/c mice. Gene Ther. 8, 447–452 (2001).
Knutson, K. L. & Disis, M. L. Expansion of HER2/neu-specific T cells ex vivo following immunization with a HER2/neu peptide-based vaccine. Clin. Breast Cancer 2, 73–79 (2001).
Sypniewska, R. K., Hoflack, L., Bearss, D. J. & Gravekamp, C. Potential mouse tumor model for pre-clinical testing of mage-specific breast cancer vaccines. Breast Cancer Res. Treat. 74, 221–233 (2002).
Manjili, M. H. et al. HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice. J. Immunol. 171, 4054–4061 (2003).
Quaglino, E. et al. Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions. J. Clin. Invest. 113, 709–717 (2004).
Xia, J. et al. Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells. J. Immunol. 170, 1980–1986 (2003).
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).
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).
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).
Sacco, M. G. et al. Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice. Gene Ther. 8, 67–70 (2001).
Nanni, P. et al. Prevention of HER-2/neu transgenic mammary carcinoma by tamoxifen plus interleukin 12. Int. J. Cancer. 105, 384–389 (2003).
Sacco, M. G. et al. Combined antiestrogen, antiangiogenic and anti-invasion therapy inhibits primary and metastatic tumor growth in the MMTVneu model of breast cancer. Gene Ther. 10, 1903–1909 (2003).
Lu, C. et al. Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors. J. Natl. Cancer Inst. 95, 1825–1833 (2003).
Siegel, P. M., Shu, W., Cardiff, R. D., Muller, W. J. & Massague, J. Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl Acad. Sci. USA 100, 8430–8435 (2003).
Yang, Y. A. et al. Lifetime exposure to a soluble TGFβ antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109, 1607–1615 (2002). Demonstration that an antagonist of TGFβ can reduce metastasis in a GEM model without serious side-effects.
Wang, D. & Dubois, R. N. Cyclooxygenase-2: a potential target in breast cancer. Semin. Oncol. 31, 64–73 (2004).
Kavanaugh, C. & Green, J. E. Celecoxib delays tumor incidence and multiplicity in the C3(1)/SV40 Large T–antigen transgenic mammary cancer model. Proc. Am. Assoc. Cancer Res. 44, R4885 (abs) (2003).
Lanza-Jacoby, S. et al. The cyclooxygenase-2 inhibitor, celecoxib, prevents the development of mammary tumors in Her-2/neu mice. Cancer Epidemiol. Biomarkers Prev. 12, 1486–1491 (2003).
Yokoyama, Y., Green, J. E., Sukhatme, V. P. & Ramakrishnan, S. Effect of endostatin on spontaneous tumorigenesis of mammary adenocarcinoma in a transgenic mouse model. Cancer Res. 60, 4362–4365 (2000).
Wigginton, J. M. et al. Complete regression of established spontaneous mammary carcinoma and the therapeutic prevention of genetically programmed neoplastic transition by IL-12/pulse IL-2: induction of local T cell infiltration, fas/fas ligand gene expression, and mammary epithelial apoptosis. J. Immunol. 166, 1156–1168 (2001). Demonstration that cytokine therapy can inhibit mammary-tumour formation and cause tumour regression in a GEM model through immune and potentially non-immune mediated mechanisms. A clinical trial was subsequently initiated.
Calvo, A., Feldman, A. L., Libutti, S. K. & Green, J. E. Adenovirus-mediated endostatin delivery results in inhibition of mammary gland tumor growth in C3(1)/SV40 T-antigen transgenic mice. Cancer Res. 62, 3934–3938 (2002).
Huh, J. -I. et al. Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through anti-angiogenic and non-antiangiogenic mechanisms. Oncogene 24, 790–800 (2005).
Li, M. et al. Chemoprevention of mammary carcinogenesis in a transgenic mouse model by α-difluoromethylornithine (DFMO) in the diet is associated with decreased cyclin D1 activity. Oncogene 22, 2568–2572 (2003).
Perkins, S. N. et al. Effects of dietary restriction on spontaneous mammabery tumorigenesis in p53-deficient Wnt-1 transgenic mice. Proc. Am. Assoc. Cancer Res. 41, A531 (abs.) (2000).
Cleary, M. P. et al. Weight-cycling decreases incidence and increases latency of mammary tumors to a greater extent than does chronic caloric restriction in mouse mammary tumor virus-transforming growth factor-α female mice. Cancer Epidemiol. Biomarkers Prev. 11, 836–843 (2002).
Jin, Z. & MacDonald, R. S. Soy isoflavones increase latency of spontaneous mammary tumors in mice. J. Nutr. 132, 3186–3190 (2002).
Hursting, S. D., Perkins, S. N., Donehower, L. A. & Davis, B. J. Cancer prevention studies in p53-deficient mice. Toxicol. Pathol. 29, 137–141 (2001).
Rao, G. N., Ney, E. & Herbert, R. A. Effect of melatonin and linolenic acid on mammary cancer in transgenic mice with c-neu breast cancer oncogene. Breast Cancer Res. Treat. 64, 287–296 (2000).
Rao, G. N., Ney, E. & Herbert, R. A. Influence of diet on mammary cancer in transgenic mice bearing an oncogene expressed in mammary tissue. Breast Cancer Res. Treat. 45, 149–158 (1997).
Albright, C. D., Salganik, R. I. & Van Dyke, T. Dietary depletion of vitamin E and vitamin A inhibits mammary tumor growth and metastasis in transgenic mice. J. Nutr. 134, 1139–1144 (2004).
Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Genet. 22, 37–43 (1999).
Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Kwak, I., Tsai, S. Y. & DeMayo, F. J. Genetically engineered mouse models for lung cancer. Annu. Rev. Physiol. 66, 647–663 (2004).
Wong, A. K. & Chin, L. An inducible melanoma model implicates a role for RAS in tumor maintenance and angiogenesis. Cancer Metastasis Rev. 19, 121–129 (2000).
Young, M. R., Yang, H. S. & Colburn, N. H. Promising molecular targets for cancer prevention: AP-1, NF-κB and Pdcd4. Trends. Mol. Med. 9, 36–41 (2003).
Bok, R. A. et al. Patterns of protease production during prostate cancer progression: proteomic evidence for cascades in a transgenic model. Prostate Cancer Prostatic Dis. 6, 272–280 (2003).
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).
Doetschman, T., Maeda, N. & Smithies, O. Targeted mutation of the Hprt gene in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 85, 8583–8587 (1988).
Capecchi, M. R. Altering the genome by homologous recombination. Science 244, 1288–1292 (1989).
Copeland, N. G., Jenkins, N. A. & Court, D. L. Recombineering: a powerful new tool for mouse functional genomics. Nature Rev. Genet. 2, 769–779 (2001). An important technology to rapidly introduce mutations into large bacterial artificial chromosome segments of DNA, which can subsequently be used to generate GEM models. This will be useful for generating new models to study molecular targets for prevention.
Sauer, B. Inducible gene targeting in mice using the Cre/lox system. Methods 14, 381–392 (1998).
Holland, E. C. & Varmus, H. E. Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc. Natl Acad. Sci. USA 95, 1218–1223 (1998).
Symolon, H., Schmelz, E. M., Dillehay, D. L. & Merrill, A. H. Dietary soy sphingolipids suppress tumorigenesis and gene expression in 1,2-dimethylhydrazine-treated CF1 mice and ApcMin/+ mice. J. Nutr. 134, 1157–1161 (2004).
Rao, C. V. et al. Chemoprevention of familial adenomatous polyposis development in the APCmin mouse model by 1,4-phenylene bis(methylene)selenocyanate. Carcinogenesis 21, 617–621 (2000).
Davis, C. D., Zeng, H. & Finley, J. W. Selenium-enriched broccoli decreases intestinal tumorigenesis in multiple intestinal neoplasia mice. J. Nutr. 132, 307–309 (2002).
Jacoby, R. F. et al. Chemoprevention of spontaneous intestinal adenomas in the Apc Min mouse model by the nonsteroidal anti-inflammatory drug piroxicam. Cancer Res. 56, 710–714 (1996).
Barnes, C. J. & Lee, M. Chemoprevention of spontaneous intestinal adenomas in the adenomatous polyposis coli Min mouse model with aspirin. Gastroenterology 114, 873–877 (1998).
Williams, J. L. et al. NO-donating aspirin inhibits intestinal carcinogenesis in Min (APCMin/+) mice. Biochem. Biophys. Res. Commun. 313, 784–788 (2004).
Maroulakou, I. G., Anver, M., Garrett, L. & Green, J. E. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc. Natl Acad. Sci. USA 91, 11236–11240 (1994).
Wu, K. et al. 9-cis-retinoic acid suppresses mammary tumorigenesis in C3(1)-simian virus 40 T antigen-transgenic mice. Clin. Cancer Res. 6, 3696–3704 (2000).
Shibata, M. A. et al. Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. Carcinogenesis 24, 453–459 (2003).
Calvo, A. et al. Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin. Int. J. Cancer 101, 224–234 (2002).
Yang, X. et al. Hormonal and dietary modulation of mammary carcinogenesis in mouse mammary tumor virus-c-erbB-2 transgenic mice. Cancer Res. 63, 2425–2433 (2003).
Folkman, J. and Kalluri, R. Cancer without disease. Nature 427, 787 (2004).
Acknowledgements
The authors greatly appreciate the constructive comments from Nancy Colburn, Glenn Merlino and Ronald Lubet. We apologize to those whose papers have contributed enormously to the field, but due to space limitations, could not be cited.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Related links
Related links
DATABASES
NATIONAL CANCER INSTITUTE
FURTHER INFORMATION
Colon Cancer Chemoprevention Database (Institut National de la Recherche Agronomique)
National Cancer Institute caArray Data Portal
National Cancer Institute Division of Cancer Prevention
National Cancer Institute Mouse Models of Human Cancer Consortium
Glossary
- CHEMOPREVENTION
-
The use of natural or synthetic compounds to prevent cancer development or progression.
- NSAIDS
-
Non-steroidal anti-inflammatory drugs reduce the inflammatory response by interfering with the production of the prostaglandins that mediate inflammation.
- TUMOUR XENOGRAFT
-
Human tumour cells grown in immuno-compromised mice.
- COMPARATIVE GENOMIC HYBRIDIZATION
-
A molecular cytogenetic method for identifying the gain or loss of large segments of chromosomal material relative to a normal (reference) genome.
- RECOMBINEERING
-
Technology using phage-based Escherichia coli recombination systems, which allows the rapid introduction of targeted mutations into bacterial artificial chromosome (BAC) clones through homologous recombination. The altered BACs can subsequently be used to generate transgenic mice through microinjection or homologous recombination.
- BACTERIAL ARTIFICIAL CHROMOSOME
-
A bacterial vector that can contain up to 200 kb of genomic DNA.
- HOMOLOGOUS RECOMBINATION
-
Exchange of homologous genetic material between different strands of DNA; this is used to introduce altered genomic pieces of DNA into the germ line of mice.
- MISMATCH REPAIR GENES
-
A set of genes that encode proteins that identify discrepancies between complimentary strands of DNA and correct the error.
Rights and permissions
About this article
Cite this article
Green, J., Hudson, T. The promise of genetically engineered mice for cancer prevention studies. Nat Rev Cancer 5, 184–198 (2005). https://doi.org/10.1038/nrc1565
Issue Date:
DOI: https://doi.org/10.1038/nrc1565
This article is cited by
-
Optimizing mouse models for precision cancer prevention
Nature Reviews Cancer (2016)
-
Critical roles of specimen type and temperature before and during fixation in the detection of phosphoproteins in breast cancer tissues
Laboratory Investigation (2015)
-
Targeting HER2 Positive Breast Cancer with Chemopreventive Agents
Current Pharmacology Reports (2015)
-
Monitoring Therapy with MEK Inhibitor U0126 in a Novel Wilms Tumor Model in Wt1 Knockout Igf2 Transgenic Mice Using 18F-FDG PET with Dual-Contrast Enhanced CT and MRI: Early Metabolic Response Without Inhibition of Tumor Growth
Molecular Imaging and Biology (2013)
-
Organotypic modelling as a means of investigating epithelial-stromal interactions during tumourigenesis
Fibrogenesis & Tissue Repair (2008)