Current Concepts and New Insights from Mouse Models of Mammary Tumors on Epithelial Mesenchymal Transition and its Synergy with Mutant p53


  • A. Piersigilli Institute of Animal Pathology, Vetsuisse, University of Bern, Switzerland
  • A. D. Borowsky Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, 4115 Primate Drive, University of California, Davis, Davis, CA 95616, USA
  • Q. Chen Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, 4115 Primate Drive, University of California, Davis, Davis, CA 95616, USA
  • N.E. Hubbard Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, 4115 Primate Drive, University of California, Davis, Davis, CA 95616, USA
  • R.D. Cardiff Department of Pathology and Laboratory Medicine and Center for Comparative Medicine, 4115 Primate Drive, University of California, Davis, Davis, CA 95616, USA



p53, EMT, metastasis, MET, breast cancer, mouse model, triple negative, claudin low.


 Epithelial Mesenchymal Transition (EMT) is the transdifferentiation of epithelial cells into a mesenchymal phenotype. This process occurs during embryogenesis but also in wound healing and in tumors. The neoplastic EMT is characterized by variably complete shedding of epithelial architectural features and acquisition of mesenchymal traits. In immunohistochemistry a variable coexpression of cytokeratins, vimentin or alpha-smooth muscle actin with loss of E-cadherin and other interepithelial adhesion molecules is characteristic. Such transition is associated with mutations both at the genetic (somatic) and epigenetic levels and is believed to confer a more advantageous phenotype for local and distant spread of cancer cells. Mammary carcinoma can exhibit EMT features in humans and mice and it tends to occur more frequently in women with tumors bearing a worse prognosis such as the claudin low subtype within the triple negative cancer. Missense mutation of TP53 is one of the most common mutations in cancer and it is frequently found in EMT tumor types, often with a more aggressive behavior. The current literature and survey of our mouse EMT cases in the Genomic Pathology Center image archives demonstrate a synergy between p53 and EMT that is independent of the initiating oncogene. However, p53 mutation is not sufficient or causal for EMT. Moreover, despite the local malignant behavior, processes such as spontaneous metastases and Mesenchymal Epithelial Transition (MET) appear not to be as frequent and obvious as previously hypothesized.


Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.

Radaelli E, Damonte P, Cardiff RD. Epithelial-mesenchymal transition in mouse mammary tumorigenesis. Future Oncol 2009; 5(8): 1113-27.

Arnoux V, Nassour M, L'Helgoualc'h A, Hipskind RA, Savagner P. Erk5 controls Slug expression and keratinocyte activation during wound healing. Mol Biol Cell 2008; 19(11): 4738-49.

Boyer B, Vallés AM, Edme N. Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol. 2000; 60(8): 1091-9.

Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 2013; 19(11): 1438-49.

D'Amato NC, Ostrander JH, Bowie ML, Sistrunk C, Borowsky A, Cardiff RD, Bell K, Young LJ, Simin K, Bachelder RE, Delrow J, Dawson A, Yee LD, Mrozek K, Clay TM, Osada T, Seewaldt VL. Evidence for phenotypic plasticity in aggressive triple-negative breast cancer: human biology is recapitulated by a novel model system. PLoS One 2012; 7(9): e45684.

Leroy P, Mostov KE. Slug is required for cell survival during partial epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 2010; 15: 117-134.

Damonte P, Gregg JP, Borowsky AD, Keister BA, Cardiff RD. EMT tumorigenesis in the mouse mammary gland. Lab Invest 2007; 87(12): 1218-26.

Cardiff RD. The pathology of EMT in mouse mammary tumorigenesis. J Mammary Gland Biol Neoplasia 2010; 15(2): 225-33.

Bednarz-Knoll N, Alix-Panabières C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev 2012; 31(3-4): 673-87.

Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A. Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron 2012; 5(1): 19-28.

Watson KD, Lai CY, Qin S, Kruse DE, Lin YC, Seo JW, Cardiff RD, Mahakian LM, Beegle J, Ingham ES, Curry FR, Reed RK, Ferrara KW. Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors. Cancer Res 2012; 72(6): 1485-93.

Bao L, Cardiff RD, Steinbach P, Messer KS, Ellies LG. Multipotent luminal mammary cancer stem cells model tumor heterogeneity. Breast Cancer Res 2015; 17(1): 137.

Dunn TB Morphology of mammary tumors in mice with and without the agent Acta Unio Int Contra Cancrorum 1951; 7 (2): 234-7

Dunn TB Morphology and histogenesis of mammary tumors. In Moulton FRe., editor. Symposium on mammary tumors in mice. Washington: Am Assoc Adv Sci 1945: 13-38.

Pulaski BA, Ostrand-Rosenberg S. Mouse 4T1 breast tumor model. Curr Protoc Immunol 2001; Chapter 20: Unit 20.2.

Nakamori M, Fu X, Rousseau R, Chen SY, Zhang X. Destruction of nonimmunogenic mammary tumor cells by a fusogenic oncolytic herpes simplex virus induces potent antitumor immunity Molecular Therapy 2004; 9(5): 658-665.

Li H, Dutuor A, Fu X, Zhang X Induction of strong antitumor immunity by an HSV-2-based oncolytic virus in a murine mammary tumor model J Gene Med 2007; 9(3): 161–169.

Tao K, Fang M, Alroy J, Gary GG. Imageable 4T1 model for the study of late stage breast cancer. BMC Cancer 2008; 8, article 228.

Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcription pathways. Cancer Res 2008; 68: 3645-54.

Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, Escrivà M, Hernandez-Munoz, Di Croce L, Helin K, Garcia de Herreros A, Peiro’ S. Polycomb complex 2 is requiredfor E-cadherin repression by the Snail1 transcription factor Mol Cell Biol 2008; 28(15): 4772-81.

Cao Q, Yu J, Dhanasekaran SM, KimJH, Mani RS, Tomlins SA, Mehra R, Laxman B, Cao X, Yu J, Kleer CG, Varambally S, Chinnaiyan AM. Repression of E-cadherin by the polcycomb group protein EZH2 in cancer. Oncogene 2008; 27(58): 7274-84.

Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011; 145(6): 926-40.

Peinhado H, Olmeda D, Cano A. Snail, Zeb and bHLH factors in tumor progression: an alliance against the epithelial phenotype? Nat Rev Cancer 2007; 7: 415-428.

Cedar H. & Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 2009; 10: 295-304.

Molofsky AV. et al. Bmi-1 dependence distinguishes neural stem cells self-renewal from progenitor proliferation. Nature 2003; 425: 962-67.

Sangiorgi E, Capecchi MR. Bmi1 is expressed in vivo in intestinal stem cells. Nat Genet 2008; 40: 915-920.

Martin A, Cano A. Tumorigenesis: Twist1 links EMT to self renewal. Nat Cell Biol 2010; 12: 924-25.

Yang MH. et al. Bmi1 is essential in Twist1- induced epithelial mesenchymal transition. Nat Cell Biol 2010; 12: 982-92.

Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell 1999; 4(2): 199-207.

D’Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, Cardiff RD, Chodosh LA. C-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med 2001; 7(2): 235-9.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2002; 2(6): 442-54.

Kimbung S, Kovács A, Danielsson A, Bendahl PO, Lövgren K, Stolt MF, Tobin NP, Lindström L, Bergh J, Einbeigi Z, Fernö M, Hatschek T, Hedenfalk I. Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications. Oncotarget 2015.

Debies MT, Gestl SA, Mathers JL, Mikse OR, Leonard TL, Moody SE, Chodosh LA, Cardiff RD, Gunther EJ. Tumor escape in a Wnt1-dependent mouse breast cancer model is enabled by p19/p53 pathway lesions but not p16 loss. J Clin Invest 2008; 118(1): 51-63.

Moody SE, Perez D, Pan TC, Sarkisian CJ, Portocarrero CP, Sterner CJ, Notorfrancesco KL, Cardiff RD, Chodosh LA. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 2005; 8(3): 197-209.

Lowe SW, Sherr CJ. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr Opin Genet Dev 2003; 13(1): 77-83.

Andrechek ER, Cardiff RD, Chang JT, Gatza ML, Acharya CR, Potti A, Nevins JR. Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential. Proc Natl Acad Sci USA 2009; 106(38): 16387-92.

Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, Rehm S, Russo J, Tavassoli FA, Wakefield LM, Ward JM, Green JE. The mammary pathology of genetically engineered mice: The consensus report and recommendations from the Annapolis meeting. Oncogene 2000; 19: 968-988.

Dandekar S, Sukumar S, Zarbl H, Young LJ, Cardiff RD. Specific activation of the cellular Harvey-ras oncogene in dimethylbenzanthracene-induced mouse mammary tumors. Mol Cell Biol 1986; 6(11): 4104-8.

Strange R, Aguilar-Cordova E, Young LJ, Billy HT, Dandekar S, Cardiff RD. Harvey-ras mediated neoplastic development in the mouse mammary gland. Oncogene 1989; 4(3): 309-15.

Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZX, Sherr DH, Seldin DC. Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors. Toxicol Pathol 2005; 33(6): 726-37.

Adams JR, Xu K, Liu JC, Agamez NM, Loch AJ, Wong RG, Wang W, Wright KL, Lane TF, Zacksenhaus E, Egan SE.Cooperation between Pik3ca and p53 mutations in mouse mammary tumor formation. Cancer Res 2011; 71(7): 2706-17.

Cardiff RD, Munn RJ, Galvez JJ. The Tumor Pathology of Genetically Engineered Mice: A New Approach to Molecular Pathology. In: Fox JG, Davisson MT, Quimby FW, Barthold SW, Newcomer CE, Smith AL, editors. The Mouse in Biomedical Research: Experimental Biology and Oncology Second ed. New York: Elsevier, Inc; 2006; p. 581-622.

Couto SS, Bolon B, Cardiff RD. Morphologic manifestations of gene-specific molecular alterations ("genetic addictions") in mouse models of disease. Vet Pathol 2012; 49(1): 116-29.

Coradini D, Fornili M, Ambrogi F, Boracchi P, Biganzoli E.TP53 mutation, epithelial-mesenchymal transition, and stemlike features in breast cancer subtypes. J Biomed Biotechnol 2012; 2012: 254085.

Powell E, Piwnica-Worms D, Piwnica-Worms H.Contribution of p53 to metastasis. Cancer Discov 2014; 4(4): 405-14.

Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM, Valentin-Vega YA, Terzian T, Caldwell LC, Strong LC, El-Naggar AK, Lozano G. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 2004; 119(6): 861-72.

Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT, Crowley D, Jacks T. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 2004; 119(6): 847-60.

Milner J, Medcalf EA. Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 1991; 65(5): 765-74.

Milner J, Medcalf EA, Cook AC. Tumor suppressor p53: analysis of wild-type and mutant p53 complexes. Mol Cell Biol 1991; 11(1): 12-9.

Sigal A, Rotter V. Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Res 2000; 60(24): 6788-93.

Bertheau P, Lehmann-Che J, Varna M, Dumay A, Poirot B, Porcher R, Turpin E, Plassa LF, de Roquancourt A, Bourstyn E, de Cremoux P, Janin A, Giacchetti S, Espié M, de Thé H. p53 in breast cancer subtypes and new insights into response to chemotherapy. Breast 2013; 22(Suppl 2): S27-9.

Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-awar R, Katona BW, Shilatifard A, Huang J, Hua X, Arrowsmith CH, Berger SL. Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 2015; 525(7568): 206-11.

Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, Pineau P, Marchio A, Palatini J, Suh SS, Alder H, Liu CG, Dejean A, Croce CM. p53 regulates epithelial-mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med 2011; 208(5): 875-83.

Rivlin N, Brosh R, Oren M, Rotter V. Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer 2011; 2(4): 466-74.

Radaelli E, Arnold A, Papanikolaou A, Garcia-Fernandez RA, Mattiello S, Scanziani E, Cardiff RD. Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol 2009; 46(4): 736-45.

Ponzo MG, Lesurf R, Petkiewicz S, O'Malley FP, Pinnaduwage D, Andrulis IL, Bull SB, Chughtai N, Zuo D, Souleimanova M, Germain D, Omeroglu A, Cardiff RD, Hallett M, Park M. Met induces mammary tumors with diverse histologies and is associated with poor outcome and human basal breast cancer. Proc Natl Acad Sci USA 2009; 106(31):

Knight JF, Lesurf R, Zhao H, Pinnaduwage D, Davis RR, Saleh SM, Zuo D, Naujokas MA, Chughtai N, Herschkowitz JI, Prat A, Mulligan AM, Muller WJ, Cardiff RD, Gregg JP, Andrulis IL, Hallett MT, Park M. Met synergizes with p53 loss to induce mammary tumors that possess features of claudin-low breast cancer. Proc Natl Acad Sci USA 2013; 110(14): E1301-10.

Liu JC, Voisin V, Wang S, Wang DY, Jones RA, Datti A, Uehling D, Al-awar R, Egan SE, Bader GD, Tsao M, Mak TW, Zacksenhaus E. Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K. EMBO Mol Med 2014; 6(12): 1542-60.

Nieto MA, Cano A. The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin Cancer Biol 2012; 22(5-6): 361-8.

Dovas A, Patsialou A, Harney AS, Condeelis J, Cox D. Imaging interactions between macrophages and tumour cells that are involved in metastasis in vivo and in vitro. J Microsc 2013; 251(3): 261-9.

Sugino T, Kusakabe T, Hoshi N, Yamaguchi T, Kawaguchi T, Goodison S, Sekimata M, Homma Y, Suzuki T. An invasion-independent pathway of blood-borne metastasis: a new murine mammary tumor model. Am J Pathol 2002; 160(6): 1973-80.

Sugino T, Yamaguchi T, Ogura G, Saito A, Hashimoto T, Hoshi N, et al. Morphological evidence for an invasion-independent metastasis pathway exists in multiple human cancers. BMC Med 2004; 2: 9.

Apolant H. Die epitheliale Geschwülste der Maus. Arbeiten ad Königlchn Inst FExptTher zu Frankfurt am M 1906; 1: 7-68.

Shi HY, Zhang W, Liang R, Abraham S, Kittrel FS, Medina D,Zhang M. Blocking tumor growth, invasion, and metastasis by maspin in a syngeneic breast cancer model. Cancer Res 2001; 61: 6945-51.

Frisch SM, Francis H. Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 1994; 124(4): 619-26.

Mukhopadhyay UK, Eves R, Jia L, Mooney P, Mak AS p53 suppresses Src-induced podosome and rosette formation and cellular invasiveness through the upregulation of caldesmon. Mol Cell Biol 2009; 29: 3088-98.

Ozdemir E, Kakehi Y, Okuno H, Habuchi T, Okada Y, Yoshida O. Strong correlation of basement membrane degradation with p53 inactivation and/or MDM2 overexpression in superficial urothelial carcinomas. J Urol 1997; 158: 206-11.

Attardi LD, Jacks T, The role of p53 in tumor suppression: lessons from mouse models. Cell Mol Life Sci 1999; 55: 48-63.

Wend P, Runke S, Wend K, Anchondo B, Yesayan M, Jardon M, Hardie N, Loddenkemper C, Ulasov I, Lesniak MS, Wolsky R, Bentolila LA, Grant SG, Elashoff D, Lehr S, Latimer JJ, Bose S, Sattar H, Krum SA, Miranda-Carboni GA. WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer. EMBO Mol Med 2013; 5(2): 264-79.

Frisch SM. The epithelial cell default-phenotype hypothesis and its implications for cancer. Bioessays 1997; 19(8): 705-9.

Di Leo A, Tanner M, Desmedt C, Paesmans M, Cardoso F, Durbecq V, Chan S, Perren T, Aapro M, Sotiriou C, Piccart MJ, Larsimont D, Isola J; TAX 303 translational study team. p-53 gene mutations as a predictive marker in a population of advanced breast cancer patients randomly treated with doxorubicin or docetaxel in the context of a phase III clinical trial. Ann Oncol 2007; 18(6): 997-1003.

Taylor NJ, Nikolaishvili-Feinberg N, Midkiff BR, Conway K , Millikan RC, Geradts J. Rational Manual and Automated Scoring Thresholds for the Immunohistochemical Detection of TP53 Missense Mutations in Human Breast Carcinomas. Appl Immunohistochem Mol Morphol 2015.

Sjögren S, Inganäs M, Norberg T, Lindgren A, Nordgren H, Holmberg L, Bergh J. The p53 gene in breast cancer: prognostic value of complementary DNA sequencing versus immunohistochemistry. J Natl Cancer Inst 1996; 88(3-4): 173-82.

Soussi T. p53 Antibodies in the sera of patients with various types of cancer: a review, Cancer Res 2000; 60(7): 1777-88.

Lehmann BD, Pietenpol JA, Clinical implications of molecular heterogeneity in triple negative breast cancer, The Breast 2015.

Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA. Subtyping of Triple-Negative Breast Cancer: Implications for Therapy Cancer 2015; 121(1): 8-16.

Hollern DP, Andrechek ER. A genomic analysis of mouse models of breast cancer reveals molecular features of mouse models and relationship to human breast cancer. Breast Cancer Res 2014; 16(3): R59.

Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A, Rimm DL, Wong H, Rodriguez A, Herschkowitz JI, Fan C, Zhang X, He X, Pavlick A, Gutierrez MC, Renshaw L, Larionov AA, Faratian D, Hilsenbeck SG, Perou CM, Lewis MT, Rosen JM, Chang JC. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 2009; 106(33): 13820-5.

Mani SA Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704-15.

Leung JY, Andrechek ER, Cardiff RD, Nevins JR. Heterogeneity in MYC induced mammary tumors contributes to escape from oncogene dependence. Oncogene 2012; 31 (20): 2545-54.

Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, Sanchez-Rivera FJ, Resnick R, Bronson R, Hemann MT, Jacks T. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 2010; 468(7323): 572-5.

Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res 2005; 65(14): 5991-5; discussion 5995.

Selivanova G. Therapeutic targeting of p53 by small molecules. Semin Cancer Biol 2010; 20(1): 46-56.

Maroulaku IG, Shibata MA, Jorcyk CL, Chen XX, Green JE. Reduced p53 dosage associated with mammary tumor metastases in C3(1)/TAG transgenic mice. Mol Carcinog 1997; 20(2): 168-74.<168::AID-MC3>3.0.CO;2-J

Parant JM, Lozano G. Disrupting TP53 in mouse models of human cancers. Hum Mutat 2003; 21: 321-6.

Chang CJ Chao CH, Xia W, Yang JY, Y Xiong, Li CW, Yu WH, Rehman SH, Hsu JL, Lee HH, Liu M, Chen CT, Yu D, Hung MC. Nat Cell Biol 2011; 13(3): 317-23.

Pinho AV, Rooman I, Real FXs. P53 dependent regulation of growth, epithelial mesenchymal transition and stemness in normal pancreatic epithelial cells. Cell Cycle 2011; 10(8): 1312-21.

Selivanova G, Wiman KG. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 2007; 26: 2243-54.




How to Cite

A. Piersigilli, A. D. Borowsky, Q. Chen, N.E. Hubbard, & R.D. Cardiff. (2015). Current Concepts and New Insights from Mouse Models of Mammary Tumors on Epithelial Mesenchymal Transition and its Synergy with Mutant p53. Journal of Analytical Oncology, 4(4),  191–206.