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
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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
SURGICAL PATHOLOGISTS
• Barry Gusterson, ICR
• Maria Merino, NIH
• Fattaneh Tassavoli, AFIP
VETERINARY PATHOLOGISTS
• Miriam Anver, NIH
• Sabine Rehm, SKBP
• Jerry Ward, NIH
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
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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
(http://pathology.ucdavis.edu/tgmice/jaxworkshop
/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 REPORT
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NOMENCLATURE
IMMUNOPHENOTYPING
NATURAL HISTORY
ROLE OF PATHOLOGY
COMPARATIVE PATHOLOGY
GEM MAMMARY TUMOR
BIOLOGY
Conclusion :
The natural history of disease is not well documented
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Neoplastic progression
Hormone dependence
Invasion
Metastasis
GEM MAMMARY TUMOR
MORPHOLOGY
• Resemble “SPONTANEOUS” mammary tumors: fgf-3, notch-3,
wnt-1,wnt-10b
• Unique GENE-SPECIFIC “SIGNATURE” PHENOTYPE: cerbB2, 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
• Descriptors
• Modifiers
• Grading
GEM MAMMARY DESCRIPTORS
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Papilliary
Solid
Glandular
Not Otherwise Specified
(NOS)
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Adenosquamous
Adeno-Myoepithelioma
Fibroadenoma
Squamous Cell
GEM MAMMARY MODIFIERS
BIOLOGICAL POTENTIAL
• Carcinoma
• Adenoma
• Intraepithelial Neoplasia
ETIOLOGY
• Genotype
• Virus-induced
• Carcinogen-induced
PROPERTY
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Secretory
Necrotic
Metaplastic
Fibrotic
TOPOGRAPHY
• Diffuse
• Focal
• Multifocal
GEM MAMMARY MODIFIERS
BIOLOGICAL POTENTIAL
• Mammary Intraepithelial Neoplasia (MIN):
1) Based on nuclear grade.
2) Opportunity to understand the biology of
progression through transplantation and
molecular studies.
ETIOLOGY
• Genotype:
myc-type, ras-type, erbB2-type, ret-type
GEM MAMMARY
IMMUNOPHENOTYING
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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
SIMILARITIES
DIFFERENCES
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Genes
Phenotypes
Progression
Metastasis
Genes
Phenotypes
Cells
Metastatic patterns
Tumor kinetics
Hormone dependence