Overview of Genetically Engineered Mouse Models of Breast Cancer Used in Translational Biology and Drug Development

Kirsty R. Greenow1, Matthew J. Smalley2

1 Current Address: Propath UK Ltd., Hereford, United Kingdom, 2 Corresponding Author: SmalleyMJ@Cardiff.ac.uk
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 14.36
DOI:  10.1002/0471141755.ph1436s70
Online Posting Date:  September, 2015
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Breast cancer is a heterogeneous condition with no single standard of treatment and no definitive method for determining whether a tumor will respond to therapy. The development of murine models that faithfully mimic specific human breast cancer subtypes is critical for the development of patientā€specific treatments. While the artificial nature of traditional in vivo xenograft models used to characterize novel anticancer treatments has limited clinical predictive value, the development of genetically engineered mouse models (GEMMs) makes it possible to study the therapeutic responses in an intact microenvironment. GEMMs have proven to be an experimentally tractable platform for evaluating the efficacy of novel therapeutic combinations and for defining the mechanisms of acquired resistance. Described in this overview are several of the more popular breast cancer GEMMs, including details on their value in elucidating the molecular mechanisms of this disorder. Ā© 2015 by John Wiley & Sons, Inc.

Keywords: Breast cancer; mouse models; luminal; HER2; triple negative

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • GEMMs of Triple‐Negative/Basal Breast Cancer
  • GEMMs of HER2‐Positive Breast Cancer
  • GEMMs of ER‐Positive Breast Cancer
  • Metastatic GEM Models of Breast Cancer
  • Summary
  • Acknowledgements
  • Conflicts of Interest
  • Literature Cited
  • Figures
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
  Ahmed, S., Sami, A., and Xiang, J. 2015. HER2‐directed therapy: Current treatment options for HER2‐positive breast cancer. Breast Cancer 22:101‐116.
  Ali, S. and Clark, A.J. 1988. Characterization of the gene encoding ovine beta‐lactoglobulin. Similarity to the genes for retinol binding protein and other secretory proteins. J. Mol. Biol. 199:415‐426.
  Allred, D.C., Brown, P., and Medina, D. 2004. The origins of estrogen receptor alpha‐positive and estrogen receptor alpha‐negative human breast cancer. Breast Cancer Res. 6:240‐245.
  Almholt, K., Lund, L.R., Rygaard, J., Nielsen, B.S., Danø, K., Rømer, J., and Johnsen, M. 2005. Reduced metastasis of transgenic mammary cancer in urokinase‐deficient mice. Int. J. Cancer 113:525‐532.
  André, F. and Zielinski, C.C. 2012. Optimal strategies for the treatment of metastatic triple‐negative breast cancer with currently approved agents. Ann. Oncol. 23:vi46‐vi51.
  Andrechek, E.R., Hardy, W.R., Siegel, P.M., Rudnicki, M.A., Cardiff, R.D., and Muller, W.J. 2000. Amplification of the neu/erbB‐2 oncogene in a mouse model of mammary tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 97:3444‐3449.
  Andrechek, E.R., Laing, M.A., Girgis‐Gabardo, A.A., Siegel, P.M., Cardiff, R.D., and Muller, W.J. 2003. 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.
  Blanco‐Aparicio, C., Perez‐Gallego, L., Pequeno, B., Leal, J.F., Renner, O., and Carnero, A. 2007. Mice expressing myrAKT1 in the mammary gland develop carcinogen‐induced ER‐positive mammary tumors that mimic human breast cancer. Carcinogenesis 28:584‐594.
  Bouchard, L., Lamarre, L., Tremblay, P.J., and Jolicoeur, P. 1989. Stochastic appearance of mammary tumors in transgenic mice carrying the MMTV/c‐neu oncogene. Cell 57:931‐936.
  Bortner, D.M. and Rosenberg, M.P. 1997. Induction of mammary gland hyperplasia and carcinomas in transgenic mice expressing human cyclin E. Mol. Cell. Biol. 17:453‐459.
  Brodie, S.G., Xu, X., Qiao, W., Li, W.M., Cao, L., and Deng, C.X. 2001. Multiple genetic changes are associated with mammary tumorigenesis in Brca1 conditional knockout mice. Oncogene 20:7514‐7523.
  Bugge, T.H., Lund, L.R., Kombrinck, K.K., Nielsen, B.S., Holmbäck, K., Drew, A.F., Flick, M.J., Witte, D.P., Danø, K., and Degen, J.L. 1998. Reduced metastasis of Polyoma virus middle T antigen‐induced mammary cancer in plasminogen‐deficient mice. Oncogene 16:3097‐3104.
  Carey, L., Winer, E., Viale, G., Cameron, D., and Gianni, L. 2010. Triple‐negative breast cancer: Disease entity or title of convenience? Nat. Rev. Clin. Oncol. 7:683‐692.
  Chan, S.R., Vermi, W., Luo, J., Lucini, L., Rickert, C., Fowler, A.M., Lonardi, S., Arthur, C., Young, L.J., Levy, D.E., Welch, M.J., Cardiff, R.D., and Schreiber, R.D. 2012. STAT1‐deficient mice spontaneously develop estrogen receptor α‐positive luminal mammary carcinomas. Breast Cancer Res. 14:R16‐R36.
  Chandarlapaty, S., Sakr, R.A., Giri, D., Patil, S., Heguy, A., Morrow, M., Modi, S., Norton, L., Rosen, N., Hudis, C., and King, T.A. 2012. Frequent mutational activation of the PI3K‐AKT pathway in trastuzumab‐resistant breast cancer. Clin. Cancer Res. 18:6784‐6791.
  Cheng, J., DeCaprio, J.A., Fluck, M.M., and Schaffhausen, B.S. 2009. Cellular transformation by simian virus 40 and murine polyoma virus T antigens. Semin. Cancer Biol. 19:218‐228.
  Cummings, S.R., Tice, J.A., Bauer, S., Browner, W.S., Cuzick, J., Ziv, E., Vogel, V., Shepherd, J., Vachon, C., Smith‐Bindman, R., and Kerlikowske, K. 2009. Prevention of breast cancer in postmenopausal women: Approaches to estimating and reducing risk. J. Natl. Cancer Inst. 101:384‐398.
  Dabydeen, S.A. and Furth, P.A. 2014. Genetically engineered ERα‐positive breast cancer mouse models. Endocr. Relat. Cancer 21:R195‐R208.
  Dankort, D., Maslikowski, B., Warner, N., Kanno, N., Kim, H., Wang, Z., Moran, M.F., Oshima, R.G., Cardiff, R.D., and Muller, W.J. 2001. 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.
  Dawson, S.J., Rueda, O.M., Aparicio, S., and Caldas, C. 2013. A new genome‐driven integrated classification of breast cancer and its implications. EMBO J. 32:617‐628.
  DeNardo, D.G., Barreto, J.B., Andreu, P., Vasquez, L., Tawfik, D., Kolhatkar, N., and Coussens, L.M. 2009. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell 16:91‐102.
  Dent, R., Trudeau, M., Pritchard, K.I., Hanna, W.M., Kahn, H.K., Sawka, C.A., Lickley, L.A., Rawlinson, E., Sun, P., and Narod, S.A. 2007. Triple‐negative breast cancer: Clinical features and patterns of recurrence. Clin. Cancer Res. 13:4429‐4434.
  Derksen, P.W., Braumuller, T.M., van der Burg, E., Hornsveld, M., Mesman, E., Wesseling, J., Krimpenfort, P., and Jonkers, J. 2011. Mammary‐specific inactivation of E‐cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice. Dis. Model. Mech. 4:347‐358.
  Diaz‐Cruz, E.S., Cabrera, M.C., Nakles, R., Rutstein, B.H., and Furth, P.A. 2010. BRCA1 deficient mouse models to study pathogenesis and therapy of triple negative breast cancer. Breast Dis. 32:85‐97.
  Drost, R.M. and Jonkers, J. 2009. Preclinical mouse models for BRCA1‐associated breast cancer. Br. J. Cancer 101:1651‐1657.
  Esteva, F.J., Guo, H., Zhang, S., Santa‐Maria, C., Stone, S., Lanchbury, J.S., Sahin, A.A., Hortobagyi, G.N., and Yu, D. 2010. PTEN, PIK3CA, p‐AKT, and p‐p70S6K status: Association with trastuzumab response and survival in patients with HER2‐positive metastatic breast cancer. Am. J. Pathol. 177:1647‐1656.
  Fantozzi, A. and Christofori, G. 2006. Mouse models of breast cancer metastasis. Breast Cancer Res. 8:212‐222.
  Fluck, M.M. and Schaffhausen, B.S. 2009. Lessons in signaling and tumorigenesis from polyomavirus middle T antigen. Microbiol. Mol. Biol. Rev. 73:542‐563.
  Fojo, T. and Bates, S. 2013. Mechanisms of resistance to PARP inhibitors—three and counting. Cancer Discov. 3:20‐23.
  Fong, P.C., Boss, D.S., Yap, T.A., Tutt, A., Wu, P., Mergui‐Roelvink, M., Mortimer, P., Swaisland, H., Lau, A., O'Connor, M.J., Ashworth, A., Carmichael, J., Kaye, S.B., Schellens, J.H., and de Bono, J.S. 2009. Inhibition of poly(ADP‐ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361:123‐134.
  Forrester, E., Chytil, A., Bierie, B., Aakre, M., Gorska, A.E., Sharif‐Afshar, A.R., Muller, W.J., and Moses, H.L. 2005. Effect of conditional knockout of the type II TGF‐beta receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis. Cancer Res. 65:2296‐2302.
  Fowler, A.M., Chan, S.R., Sharp, T.L., Fettig, N.M., Zhou, D., Dence, C.S., Carlson, K.E., Jeyakumar, M., Katzenellenbogen, J.A., Schreiber, R.D., and Welch, M.J. 2012. Small‐animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer. J. Nucl. Med. 53:1119‐1126.
  Gasco, M., Shami, S., and Crook, T. 2002. The p53 pathway in breast cancer. Breast Cancer Res. 4:70‐76.
  Gouon‐Evans, V., Rothenberg, M.E., and Pollard, J.W. 2000. Postnatal mammary gland development requires macrophages and eosinophils. Development 127:2269‐2282.
  Guy, C.T., Cardiff, R.D., and Muller, W.J. 1992. Induction of mammary tumors by expression of polyomavirus middle T oncogene: A transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12:954‐961.
  Guy, C.T., Cardiff, R.D., and Muller, W.J. 1996. Activated neu induces rapid tumor progression. J. Biol. Chem. 271:7673‐7678.
  Habashy, H.O., Powe, D.G., Abdel‐Fatah, T.M., Gee, J.M., Nicholson, R.I., Green, A.R., Rakha, E.A., and Ellis, I.O. 2012. A review of the biological and clinical characteristics of luminal‐like oestrogen receptor‐positive breast cancer. Histopathology 60:854‐863.
  Hanker, A.B., Pfefferle, A.D., Balko, J.M., Kuba, M.G., Young, C.D., Sánchez, V., Sutton, C.R., Cheng, H., Perou, C.M., Zhao, J.J., Cook, R.S., and Arteaga, C.L. 2013. Mutant PIK3CA accelerates HER2‐driven transgenic mammary tumors and induces resistance to combinations of anti‐HER2 therapies. Proc. Natl. Acad. Sci. U.S.A. 110:14372‐14377.
  Hay, T., Matthews, J.R., Pietzka, L., Lau, A., Cranston, A., Nygren, A.O., Douglas‐Jones, A., Smith, G.C., Martin, N.M., O'Connor, M., and Clarke, A.R. 2009. Poly(ADP‐ribose) polymerase‐1 inhibitor treatment regresses autochthonous Brca2/p53‐mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 69:3850‐3855.
  Hennighausen, L. 1990. The mammary gland as a bioreactor: production of foreign proteins in milk. Protein Expr. Purif. 1:3‐8.
  Hodgson, J.G., Malek, T., Bornstein, S., Hariono, S., Ginzinger, D.G., Muller, W.J., and Gray, J.W. 2005. Copy number aberrations in mouse breast tumors reveal loci and genes important in tumorigenic receptor tyrosine kinase signaling. Cancer Res. 65:9695‐9704.
  Holstege, H., van Beers, E., Velds, A., Liu, X., Joosse, S.A., Klarenbeek, S., Schut, E., Kerkhoven, R., Klijn, C.N., Wessels, L.F., Nederlof, P.M., and Jonkers, J. 2010. Cross‐species comparison of aCGH data from mouse and human BRCA1‐ and BRCA2‐mutated breast cancers. BMC Cancer 10:455‐470.
  Hu, Y., Sun, H., Drake, J., Kittrell, F., Abba, M.C., Deng, L., Gaddis, S., Sahin, A., Baggerly, K., Medina, D., and Aldaz, C.M. 2004. From mice to humans: Identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. Cancer Res. 64:7748‐7755.
  Jabrane‐Ferrat, N., Campbell, M.J., Esserman, L.J., and Peterlin, B.M. 2006. Challenge with mammary tumor cells expressing MHC class II and CD80 prevents the development of spontaneously arising tumors in MMTV‐neu transgenic mice. Cancer Gene Ther. 13:1002‐1010.
  Jonkers, J. and Berns, A. 2002. Conditional mouse models of sporadic cancer. Nat. Rev. Cancer 2:251‐265.
  Jonkers, J., Meuwissen, R., vander Gulden, H., Peterse, H., van der Valk, M., and Berns, A. 2001. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29:418‐425.
  Julien, S.G., Dubé, N., Read, M., Penney, J., Paquet, M., Han, Y., Kennedy, B.P., Muller, W.J., and Tremblay, M.L. 2007. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2‐induced mammary tumorigenesis and protects from lung metastasis. Nat. Genet. 39:338‐346.
  Juvekar, A., Burga, L.N., Hu, H., Lunsford, E.P., Ibrahim, Y.H., Balmañà, J., Rajendran, A., Papa, A., Spencer, K., Lyssiotis, C.A., Nardella, C., Pandolfi, P.P., Baselga, J., Scully, R., Asara, J.M., Cantley, L.C., and Wulf, G.M. 2012. Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1‐related breast cancer. Cancer Discov. 2:1048‐1063.
  Kassam, F., Enright, K., Dent, R., Dranitsaris, G., Myers, J., Flynn, C., Fralick, M., Kumar, R., and Clemons, M. 2009. Survival outcomes for patients with metastatic triple‐negative breast cancer: Implications for clinical practice and trial design. Clin. Breast Cancer 9:29‐33.
  Knudsen, S., Jensen, T., Hansen, A., Mazin, W., Lindemann, J., Kuter, I., Laing, N., and Anderson, E. 2014. Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients. PLoS One 9:e87415.
  Kola, I. and Landis, J. 2004. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov. 3:711‐715.
  Lakhani, S.R., Reis‐Filho, J.S., Fulford, L., Penault‐Llorca, F., van der Vijver, M., Parry, S., Bishop, T., Benitez, J., Rivas, C., Bignon, Y.J., Chang‐Claude, J., Hamann, U., Cornelisse, C.J., Devilee, P., Beckmann, M.W., Nestle‐Krämling, C., Daly, P.A., Haites, N., Varley, J., Lalloo, F., Evans, G., Maugard, C., Meijers‐Heijboer, H., Klijn, J.G., Olah, E., Gusterson, B.A., Pilotti, S., Radice, P., Scherneck, S., Sobol, H., Jacquemier, J., Wagner, T., Peto, J., Stratton, M.R., McGuffog, L., Easton, D.F., and Consortium, B.C.L. 2005. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin. Cancer Res. 11:5175‐5180.
  Lemoine, N.R., Staddon, S., Dickson, C., Barnes, D.M., and Gullick, W.J. 1990. Absence of activating transmembrane mutations in the c‐erbB‐2 proto‐oncogene in human breast cancer. Oncogene 5:237‐239.
  Li, M.L. and Greenberg, R.A. 2012. Links between genome integrity and BRCA1 tumor suppression. Trends Biochem. Sci. 37:418‐424.
  Lim, E., Vaillant, F., Wu, D., Forrest, N.C., Pal, B., Hart, A.H., Asselin‐Labat, M.L., Gyorki, D.E., Ward, T., Partanen, A., Feleppa, F., Huschtscha, L.I., Thorne, H.J., Fox, S.B., Yan, M., French, J.D., Brown, M.A., Smyth, G.K., Visvader, J.E., Lindeman, G.J., and kConFab. 2009. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat. Med. 15:907‐913.
  Lin, E.Y., Nguyen, A.V., Russell, R.G., and Pollard, J.W. 2001. Colony‐stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193:727‐740.
  Lin, E.Y., Jones, J.G., Li, P., Zhu, L., Whitney, K.D., Muller, W.J., and Pollard, J.W. 2003. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163:2113‐2126.
  Lin, S.C., Lee, K.F., Nikitin, A.Y., Hilsenbeck, S.G., Cardiff, R.D., Li, A., Kang, K.W., Frank, S.A., Lee, W.H., and Lee, E.Y. 2004. Somatic mutation of p53 leads to estrogen receptor alpha‐positive and ‐negative mouse mammary tumors with high frequency of metastasis. Cancer Res. 64:3525‐3532.
  Lipnik, K., Petznek, H., Renner‐Müller, I., Egerbacher, M., Url, A., Salmons, B., Günzburg, W.H., and Hohenadl, C. 2005. A 470 bp WAP‐promoter fragment confers lactation independent, progesterone regulated mammary‐specific gene expression in transgenic mice. Transgenic Res. 14:145‐158.
  Liu, X., Holstege, H., van der Gulden, H., Treur‐Mulder, M., Zevenhoven, J., Velds, A., Kerkhoven, R.M., van Vliet, M.H., Wessels, L.F., Peterse, J.L., Berns, A., and Jonkers, J. 2007. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1‐mutated basal‐like breast cancer. Proc. Natl. Acad. Sci. U.S.A. 104:12111‐12116.
  Lopez, J.I., Camenisch, T.D., Stevens, M.V., Sands, B.J., McDonald, J., and Schroeder, J.A. 2005. CD44 attenuates metastatic invasion during breast cancer progression. Cancer Res. 65:6755‐6763.
  Ma, Z., Gibson, S.L., Byrne, M.A., Zhang, J., White, M.F., and Shaw, L.M. 2006. Suppression of insulin receptor substrate 1 (IRS‐1) promotes mammary tumor metastasis. Mol. Cell Biol. 26:9338‐9351.
  Maglione, J.E., Moghanaki, D., Young, L.J., Manner, C.K., Ellies, L.G., Joseph, S.O., Nicholson, B., Cardiff, R.D., and MacLeod, C.L. 2001. Transgenic Polyoma middle‐T mice model premalignant mammary disease. Cancer Res. 61:8298‐8305.
  Malhotra, G.K., Zhao, X., Band, H., and Band, V. 2010. Histological, molecular and functional subtypes of breast cancers. Cancer Biol. Ther. 10:955‐960.
  Maroulakou, I.G., Oemler, W., Naber, S.P., and Tsichlis, P.N. 2007. Akt1 ablation inhibits, whereas Akt2 ablation accelerates, the development of mammary adenocarcinomas in mouse mammary tumor virus (MMTV)‐ErbB2/neu and MMTV‐polyoma middle T transgenic mice. Cancer Res. 67:167‐177.
  McCarthy, A., Savage, K., Gabriel, A., Naceur, C., Reis‐Filho, J.S., and Ashworth, A. 2007. A mouse model of basal‐like breast carcinoma with metaplastic elements. J. Pathol. 211:389‐398.
  McTiernan, A., Porter, P., and Potter, J.D. 2008. Breast cancer prevention in countries with diverse resources. Cancer 113:2325‐2330.
  Melchor, L., Molyneux, G., Mackay, A., Magnay, F.A., Atienza, M., Kendrick, H., Nava‐Rodrigues, D., López‐García, M., Milanezi, F., Greenow, K., Robertson, D., Palacios, J., Reis‐Filho, J.S., and Smalley, M.J. 2014. Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models. J. Pathol. 233:124‐137.
  Molyneux, G., Geyer, F.C., Magnay, F.A., McCarthy, A., Kendrick, H., Natrajan, R., Mackay, A., Grigoriadis, A., Tutt, A., Ashworth, A., Reis‐Filho, J.S., and Smalley, M.J. 2010. BRCA1 basal‐like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7:403‐417.
  Montagna, C., Andrechek, E.R., Padilla‐Nash, H., Muller, W.J., and Ried, T. 2002. 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.
  Muller, W.J., Sinn, E., Pattengale, P.K., Wallace, R., and Leder, P. 1988. Single‐step induction of mammary adenocarcinoma in transgenic mice bearing the activated c‐neu oncogene. Cell 54:105‐115.
  Muraoka, R.S., Koh, Y., Roebuck, L.R., Sanders, M.E., Brantley‐Sieders, D., Gorska, A.E., Moses, H.L., and Arteaga, C.L. 2003. Increased malignancy of Neu‐induced mammary tumors overexpressing active transforming growth factor beta1. Mol. Cell Biol. 23:8691‐8703.
  Muraoka‐Cook, R.S., Kurokawa, H., Koh, Y., Forbes, J.T., Roebuck, L.R., Barcellos‐Hoff, M.H., Moody, S.E., Chodosh, L.A., and Arteaga, C.L. 2004. Conditional overexpression of active transforming growth factor beta1 in vivo accelerates metastases of transgenic mammary tumors. Cancer Res. 64:9002‐9011.
  Palacios, J., Honrado, E., Osorio, A., Cazorla, A., Sarrió, D., Barroso, A., Rodríguez, S., Cigudosa, J.C., Diez, O., Alonso, C., Lerma, E., Sánchez, L., Rivas, C., and Benítez, J. 2003. Immunohistochemical characteristics defined by tissue microarray of hereditary breast cancer not attributable to BRCA1 or BRCA2 mutations: Differences from breast carcinomas arising in BRCA1 and BRCA2 mutation carriers. Clin. Cancer Res. 9:3606‐3614.
  Park, C.Y., Min, K.N., Son, J.Y., Park, S.Y., Nam, J.S., Kim, D.K., and Sheen, Y.Y. 2014. An novel inhibitor of TGF‐β type I receptor, IN‐1130, blocks breast cancer lung metastasis through inhibition of epithelial‐mesenchymal transition. Cancer Lett. 351:72‐80.
  Parker, J.S., Mullins, M., Cheang, M.C., Leung, S., Voduc, D., Vickery, T., Davies, S., Fauron, C., He, X., Hu, Z., Quackenbush, J.F., Stijleman, I.J., Palazzo, J., Marron, J.S., Nobel, A.B., Mardis, E., Nielsen, T.O., Ellis, M.J., Perou, C.M., and Bernard, P.S. 2009. Supervised risk predictor of breast cancer based on intrinsic subtypes. J. Clin. Oncol. 27:1160‐1167.
  Perou, C.M., Sørlie, T., Eisen, M.B., van de Rijn, M., Jeffrey, S.S., Rees, C.A., Pollack, J.R., Ross, D.T., Johnsen, H., Akslen, L.A., Fluge, O., Pergamenschikov, A., Williams, C., Zhu, S.X., Lønning, P.E., Børresen‐Dale, A.L., Brown, P.O., and Botstein, D. 2000. Molecular portraits of human breast tumours. Nature 406:747‐752.
  Piccart‐Gebhart, M.J., Procter, M., Leyland‐Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., Cameron, D., Dowsett, M., Barrios, C.H., Steger, G., Huang, C.S., Andersson, M., Inbar, M., Lichinitser, M., Láng, I., Nitz, U., Iwata, H., Thomssen, C., Lohrisch, C., Suter, T.M., Rüschoff, J., Suto, T., Greatorex, V., Ward, C., Straehle, C., McFadden, E., Dolci, M.S., Gelber, R.D., and Team, H.A.H.T.S. 2005. Trastuzumab after adjuvant chemotherapy in HER2‐positive breast cancer. N. Engl. J. Med. 353:1659‐1672.
  Prat, A. and Perou, C.M. 2011. Deconstructing the molecular portraits of breast cancer. Mol. Oncol. 5:5‐23.
  Prat, A., Parker, J.S., Karginova, O., Fan, C., Livasy, C., Herschkowitz, J.I., He, X., and Perou, C.M. 2010. Phenotypic and molecular characterization of the claudin‐low intrinsic subtype of breast cancer. Breast Cancer Res. 12:R68‐R85.
  Reis‐Filho, J.S. and Tutt, A.N. 2008. Triple negative tumours: A critical review. Histopathology 52:108‐118.
  Robert, N., Leyland‐Jones, B., Asmar, L., Belt, R., Ilegbodu, D., Loesch, D., Raju, R., Valentine, E., Sayre, R., Cobleigh, M., Albain, K., McCullough, C., Fuchs, L., and Slamon, D. 2006. 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.
  Romond, E.H., Perez, E.A., Bryant, J., Suman, V.J., Geyer, C.E., Davidson, N.E., Tan‐Chiu, E., Martino, S., Paik, S., Kaufman, P.A., Swain, S.M., Pisansky, T.M., Fehrenbacher, L., Kutteh, L.A., Vogel, V.G., Visscher, D.W., Yothers, G., Jenkins, R.B., Brown, A.M., Dakhil, S.R., Mamounas, E.P., Lingle, W.L., Klein, P.M., Ingle, J.N., and Wolmark, N. 2005. Trastuzumab plus adjuvant chemotherapy for operable HER2‐positive breast cancer. N Engl. J. Med. 353:1673‐1684.
  Roop, R.P. and Ma, C.X. 2012. Endocrine resistance in breast cancer: Molecular pathways and rational development of targeted therapies. Future Oncol. 8:273‐292.
  Rosen, E.M. and Pishvaian, M.J. 2014. Targeting the BRCA1/2 tumor suppressors. Curr. Drug. Targets 15:17‐31.
  Rottenberg, S. and Jonkers, J. 2008. Modeling therapy resistance in genetically engineered mouse cancer models. Drug Resist. Update 11:51‐60.
  Rottenberg, S., Nygren, A.O., Pajic, M., van Leeuwen, F.W., van der Heijden, I., van de Wetering, K., Liu, X., de Visser, K.E., Gilhuijs, K.G., van Tellingen, O., Schouten, J.P., Jonkers, J., and Borst, P. 2007. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl. Acad. Sci. U.S.A. 104:12117‐12122.
  Rottenberg, S., Jaspers, J.E., Kersbergen, A., van der Burg, E., Nygren, A.O., Zander, S.A., Derksen, P.W., de Bruin, M., Zevenhoven, J., Lau, A., Boulter, R., Cranston, A., O'Connor, M.J., Martin, N.M., Borst, P., and Jonkers, J. 2008. High sensitivity of BRCA1‐deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. U.S.A. 105:17079‐17084.
  Rouzier, R., Perou, C.M., Symmans, W.F., Ibrahim, N., Cristofanilli, M., Anderson, K., Hess, K.R., Stec, J., Ayers, M., Wagner, P., Morandi, P., Fan, C., Rabiul, I., Ross, J.S., Hortobagyi, G.N., and Pusztai, L. 2005. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin. Cancer Res. 11:5678‐5685.
  Schoeffner, D.J., Matheny, S.L., Akahane, T., Factor, V., Berry, A., Merlino, G., and Thorgeirsson, U.P. 2005. VEGF contributes to mammary tumor growth in transgenic mice through paracrine and autocrine mechanisms. Lab. Invest. 85:608‐623.
  Sharpless, N.E. and Depinho, R.A. 2006. The mighty mouse: Genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5:741‐754.
  Siegel, P.M. and Massagué, J. 2003. Cytostatic and apoptotic actions of TGF‐beta in homeostasis and cancer. Nat. Rev. Cancer 3:807‐821.
  Siegel, P.M. and Muller, W.J. 1996. Mutations affecting conserved cysteine residues within the extracellular domain of Neu promote receptor dimerization and activation. Proc. Natl. Acad. Sci. U.S.A. 93:8878‐8883.
  Siegel, P.M., Dankort, D.L., Hardy, W.R., and Muller, W.J. 1994. Novel activating mutations in the neu proto‐oncogene involved in induction of mammary tumors. Mol. Cell Biol. 14:7068‐7077.
  Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J., and Massagué, J. 2003. Transforming growth factor beta signaling impairs Neu‐induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl. Acad. Sci. U.S.A. 100:8430‐8435.
  Slamon, D.J., Clark, G.M., Wong, S.G., Levin, W.J., Ullrich, A., and McGuire, W.L. 1987. Human breast cancer: Correlation of relapse and survival with amplification of the HER‐2/neu oncogene. Science 235:177‐182.
  Sorlie, T., Tibshirani, R., Parker, J., Hastie, T., Marron, J.S., Nobel, A., Deng, S., Johnsen, H., Pesich, R., Geisler, S., Demeter, J., Perou, C.M., Lønning, P.E., Brown, P.O., Børresen‐Dale, A.L., and Botstein, D. 2003. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. U.S.A. 100:8418‐8423.
  Uji, K., Naoi, Y., Kagara, N., Shimoda, M., Shimomura, A., Maruyama, N., Shimazu, K., Kim, S.J., and Noguchi, S. 2014. Significance of TP53 mutations determined by next‐generation “deep” sequencing in prognosis of estrogen receptor‐positive breast cancer. Cancer Lett. 342:19‐26.
  Ursini‐Siegel, J., Schade, B., Cardiff, R.D., and Muller, W.J. 2007. Insights from transgenic mouse models of ERBB2‐induced breast cancer. Nat. Rev. Cancer 7:389‐397.
  van Miltenburg, M.H. and Jonkers, J. 2012. Using genetically engineered mouse models to validate candidate cancer genes and test new therapeutic approaches. Curr. Opin. Genet. Dev. 22:21‐27.
  Wagner, K.U. 2004. Models of breast cancer: Quo vadis, animal modeling? Breast Cancer Res. 6:31‐38.
  Wagner, K.U., McAllister, K., Ward, T., Davis, B., Wiseman, R., and Hennighausen, L. 2001. 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.
  Welm, A.L., Sneddon, J.B., Taylor, C., Nuyten, D.S., van de Vijver, M.J., Hasegawa, B.H., and Bishop, J.M. 2007. The macrophage‐stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans. Proc. Natl. Acad. Sci. U.S.A. 104:7570‐7575.
  Wijnhoven, S.W., Zwart, E., Speksnijder, E.N., Beems, R.B., Olive, K.P., Tuveson, D.A., Jonkers, J., Schaap, M.M., van den Berg, J., Jacks, T., van Steeg, H., and de Vries, A. 2005. Mice expressing a mammary gland‐specific R270H mutation in the p53 tumor suppressor gene mimic human breast cancer development. Cancer Res. 65:8166‐8173.
  Wyckoff, J., Wang, W., Lin, E.Y., Wang, Y., Pixley, F., Stanley, E.R., Graf, T., Pollard, J.W., Segall, J., and Condeelis, J. 2004. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors. Cancer Res. 64:7022‐7029.
  Xu, X., Wagner, K.U., Larson, D., Weaver, Z., Li, C., Ried, T., Hennighausen, L., Wynshaw‐Boris, A., and Deng, C.X. 1999. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 22:37‐43.
  Yamamoto, M., Hosoda, M., Nakano, K., Jia, S., Hatanaka, K.C., Takakuwa, E., Hatanaka, Y., Matsuno, Y., and Yamashita, H. 2014. p53 accumulation is a strong predictor of recurrence in estrogen receptor‐positive breast cancer patients treated with aromatase inhibitors. Cancer Sci. 105:81‐88.
  Yang, Y.A., Dukhanina, O., Tang, B., Mamura, M., Letterio, J.J., MacGregor, J., Patel, S.C., Khozin, S., Liu, Z.Y., Green, J., Anver, M.R., Merlino, G., and Wakefield, L.M. 2002. Lifetime exposure to a soluble TGF‐β antagonist protects mice against metastasis without adverse side effects. J. Clin. Invest. 109:1607‐1615.
  Yin, J.J., Selander, K., Chirgwin, J.M., Dallas, M., Grubbs, B.G., Wieser, R., Massagué, J., Mundy, G.R., and Guise, T.A. 1999. TGF‐β signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J. Clin. Invest. 103:197‐206.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library