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

Jackson Lab Tutorial Tissue Preparation Sampling: –Adjacent tissue –Interface between host and tumor –Contralateral mammary gland –Metastatic survey Fixation –Volume –Type –Time

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

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

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

Jackson Lab Tutorial Annapolis Recommendations (anNapolis Nine) Web-based workbook ( /syllabus/frameset1.html) Hands-on Tutorial: –Sampling and fixation –Malignancy (when is a tumor malignant?) –MIN

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

ANNAPOLIS ANNAPOLIS REPORT NOMENCLATURENOMENCLATURE IMMUNOPHENOTYPINGIMMUNOPHENOTYPING NATURAL HISTORYNATURAL HISTORY ROLE OF PATHOLOGYROLE OF PATHOLOGY COMPARATIVE PATHOLOGYCOMPARATIVE PATHOLOGY

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

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

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

GEM MAMMARY NOMENCLATURE DescriptorsDescriptors ModifiersModifiers GradingGrading

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

GEM MAMMARY MODIFIERS Carcinoma Adenoma Intraepithelial Neoplasia Secretory Necrotic Metaplastic Fibrotic Diffuse Focal Multifocal Genotype Virus-induced Carcinogen-induced BIOLOGICAL POTENTIALPROPERTY ETIOLOGYTOPOGRAPHY

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

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

GEM MAMMARY BIOLOGY Experimental Clinical-Natural History Pathology

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.

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

COMPARATIVE PATHOLOGY Genes Phenotypes Progression Metastasis Genes Phenotypes Cells Metastatic patterns Tumor kinetics Hormone dependence SIMILARITIESDIFFERENCES