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MOUSE MODELS OF HUMAN BREAST CANCER

A Report from the Annapolis Meeting Presented by Robert D. Cardiff, M.D., Ph.D. MOUSE MODELS OF HUMAN BREAST CANCER. Miriam Anver, NIH Robert Cardiff, UCD Roy Jensen, VUMC Barry Gusterson, ICR Maria Merino, NIH Sabine Rehm, SKBP Jose Russo, FCCC Fattaneh Tassavoli, AFIP

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MOUSE MODELS OF HUMAN BREAST CANCER

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  1. A Report from the Annapolis Meeting Presented by Robert D. Cardiff, M.D., Ph.D. MOUSE MODELS OF HUMAN BREAST CANCER

  2. Miriam Anver, NIH Robert Cardiff, UCD Roy Jensen, VUMC Barry Gusterson, ICR Maria Merino, NIH Sabine Rehm, SKBP Jose Russo, FCCC Fattaneh Tassavoli, AFIP Jerry Ward, NIH ANNAPOLIS PATHOLOGY PANEL

  3. Barry Gusterson, ICR Maria Merino, NIH Fattaneh Tassavoli, AFIP Miriam Anver, NIH Sabine Rehm, SKBP Jerry Ward, NIH ANNAPOLIS PATHOLOGY PANEL SURGICAL PATHOLOGISTS VETERINARY PATHOLOGISTS EXPERIMENTAL BREAST PATHOLOGISTS • Jose Russo, FCCC • Roy Jensen, VUMC • Robert Cardiff, UCD

  4. ANNAPOLIS SLIDE SET • 175 slides • 26 genes, 25 with mammary tumors • 39 genetically engineered mouse (GEM) models • 3 transplant models • 2 chemical carcinogen models • 2 species (rat and mouse) • 5 promoter systems

  5. U.C.D. TRANSGENICPATHOLOGY FACILITY • Total cases = 7392 • Mice with mammary tumors = 1187 • Mammary tumors =2112 • Strains =89 • Labs > 100; Investigators >200; Countries =8

  6. Jackson Lab Tutorial • Annapolis Recommendations (anNapolis Nine) • Web-based workbook (http://pathology.ucdavis.edu/tgmice/jaxworkshop/syllabus/frameset1.html) • Hands-on Tutorial: • Sampling and fixation • Malignancy (when is a tumor malignant?) • MIN

  7. Jackson Lab Tutorial http://pathology.ucdavis.edu/tgmice/jaxworkshop/syllabus/frameset1.html

  8. ANNAPOLIS REPORT • NOMENCLATURE • IMMUNOPHENOTYPING • NATURAL HISTORY • ROLE OF PATHOLOGY • COMPARATIVE PATHOLOGY

  9. GEM MAMMARY TUMOR BIOLOGY Conclusion : The natural history of disease is not well documented • Neoplastic progression • Hormone dependence • Invasion • Metastasis

  10. GEM MAMMARY TUMOR MORPHOLOGY • Resemble “SPONTANEOUS” mammary tumors: fgf-3, notch-3, wnt-1,wnt-10b • Unique GENE-SPECIFIC “SIGNATURE” PHENOTYPE: c-erbB2, myc, ras, IGF-2, SV40 Tag, ret-1, others • Mimic HUMAN BREAST CANCER: c-erbB2, src, myc, SV40 Tag, IGFr-2, others

  11. GEM MAMMARY PATHOLOGY • Conclusions: • Genetically engineered mice have unique pathological lesions • The natural history of disease is unknown • Current classifications do not accurately describe transgenic lesions. RECOMMENDATION: A descriptive nomenclature be adopted

  12. GEM MAMMARY NOMENCLATURE • Descriptors • Modifiers • Grading

  13. Papilliary Solid Glandular Not Otherwise Specified (NOS) Adenosquamous Adeno-Myoepithelioma Fibroadenoma Squamous Cell GEM MAMMARY DESCRIPTORS

  14. Carcinoma Adenoma Intraepithelial Neoplasia Secretory Necrotic Metaplastic Fibrotic GEM MAMMARY MODIFIERS BIOLOGICAL POTENTIAL PROPERTY ETIOLOGY TOPOGRAPHY • Genotype • Virus-induced • Carcinogen-induced • Diffuse • Focal • Multifocal

  15. Mammary Intraepithelial Neoplasia (MIN): 1) Based on nuclear grade. 2) Opportunity to understand the biology of progression through transplantation and molecular studies. GEM MAMMARY MODIFIERS BIOLOGICAL POTENTIAL ETIOLOGY • Genotype: • myc-type, ras-type, erbB2-type, ret-type

  16. GEM MAMMARY IMMUNOPHENOTYING • Transgene Expression: IHC, ISH • Nuclear Receptors: ER, PR • Myoepithelium: Smooth Muscle Actin • Luminal Cell: CK, EMA, c-erbB2, MUC-1 • Basement Membrane: Laminin, d-PAS • Other: Neuroendocrine, proliferation, p53

  17. GEM MAMMARY BIOLOGY • Experimental • Clinical-Natural History • Pathology

  18. PATHOLOGY Interpretation of morphologic alterations requires knowledge of and integration of structure, function, natural history, etiology and clinical context. Armed with this information, the pathology provides integrative biology. Without this information, histological interpretation is useless.

  19. RECOMMENDATIONS • NOMENCLATURE: Descriptive • BIOLOGY: Natural history • PATHOLOGY: Interactive research design and assessment

  20. Genes Phenotypes Progression Metastasis Genes Phenotypes Cells Metastatic patterns Tumor kinetics Hormone dependence COMPARATIVE PATHOLOGY SIMILARITIES DIFFERENCES

  21. Sampling: Adjacent tissue Interface between host and tumor Contralateral mammary gland Metastatic survey Fixation Volume Type Time Jackson Lab TutorialTissue Preparation

  22. Jackson Lab Tutorial • Neoplasms (Benign VS Malignant): • Metastasis • Pulmonary adenomas • Emboli • Colonization • Growth (Expansile vs. Invasive) • Cytological Grade • MIN (Mammary Intraepithelial Neoplasia)

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