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Normal Tissue

Modelling Human Cancer in the Mouse. GENETIC BACKGROUND. Benign Tumor. Invasive Tumor. Metastasis. Therapy. Relapse. Somatic mutations. Heterogeneous mouse population. Tumor induction Carcinogen GEMM. Normal Tissue. Exposure to Carcinogens, promoters. Angiogenesis, stromal cells

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Normal Tissue

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  1. Modelling Human Cancer in the Mouse GENETIC BACKGROUND Benign Tumor Invasive Tumor Metastasis Therapy Relapse Somatic mutations Heterogeneous mouse population Tumor induction Carcinogen GEMM Normal Tissue Exposure to Carcinogens, promoters Angiogenesis, stromal cells Immune system Inflammation

  2. Summary Chemical carcinogen models Radiation models Lifestyle models Susceptibility

  3. Epidermal Cell Initiated Cell Benign Tumor Malignant Tumor Metastatic Tumor DMBA TPA papilloma Initiation Promotion Progression Hras mut Multistage skin carcinogenesis Mutant Ras amplification Loss of wt Ras Invasion Epithelial-mesenchymal Transition (EMT) Metastasis

  4. Ras Mutations in Human Cancer Sanger Center COSMIC database (www.sanger.ac.uk/genetics/CGP/cosmic/)

  5. mutant CARCINOGEN-INDUCED H-RAS MUTATIONS IN SKIN TUMORS Quintanilla et al p c c c c c c c H-ras normal

  6. H-ras and skin cancer (circa 1982- 1986) 1. Skin tumors induced by the same carcinogen carry the sameoncogene: H-ras 2. Skin tumors induced by DMBA have the sameactivating mutation in H-ras 3. Mutations occur early – at time of initiation 4. Amplification of mutant ras or loss of wild type ras occurs during progression 5. Tumours from F1 hybrid mice show preferential mutation of one parental allele 6. Some mouse strains are resistant to ras-initiated tumours.

  7. Urethane DMBA TPA Lung Adenomas 90% K-ras mutations Skin papillomas/carcinomas 90% H-ras mutations Tissue-specific Ras mutations Conclusions: H-ras is required for skin, and K-ras for lung tumors

  8. Radiation Double-stranded breaks in DNA BRCA1 Familial breast and ovarian cancer p53 Li-Fraumeni syndrome CDS1/CHK2 Li-Fraumeni syndrome ATM Ataxia telangiectasia NBS1-MRE11-RAD50 Nijmegen breakage syndrome Ataxia-telangiectasia-like disorder Cell-cycle checkpoints DNA repair

  9. P53+/- Delta P p53m/m 4Gy 4Gy OR Fbxw7+/- Lymphomas Sarcomas Solid tumors Mouse genetic models for radiation-induced cancers 4Gy NO tumors Kemp et al, p53 deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nature Genetics, 8(1):66-69 (1994)

  10. p53+/- mice are extremely susceptible to radiation-induced tumorigenesis Kemp et al, Nat.Genet, 1994

  11. Genetic background affects radiation-induced lymphoma susceptibility

  12. 　Genetic changes in radiation-induced tumors HipK2 P53-independent Fbxw7/Cdc4 STK15: Mitotic checkpoint Notch1 Ikaros 17 18 19 X 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 0 Scc6 Par4 Msmr1 Sluc13 Skts9 Sluc7 Rmv1,2,3 Scc8 10 Rmcf Pas4 Rfv1,2 Tgct1 Lts1 Skts5 Ter Lyr2 Rfv3 Pas3 Sluc10 Rrs Sluc14 Gct2 20 Skts3 Hcf1 Scc5 Hcr2 Skts10 Hcs1 Liver Pgct1 Esl1 Hcs6 Scc2 Skts1 Rgv1 Lyr1 Par3 Gct3 30 Msmr2 Gct4 Fv4 Foc1 Foc1 Sluc4 Pas7 Pas6 Ccs1 Skts11 Ril1 Scc4 Pas9 (Pas5) Par2 40 Ots1 Rfv3 Esl1 Hcr1 Pas6 Sluc1 Tlag1 Pas5b Pctr1 Skts6 Scc1 Par1 Hcs5 Papg1 50 Sluc11 Hcs2 Hcs3 Skts7 Sluc12 Sluc9 Sluc6 Lyr3 Sluc3 Fv2 Tlsr2 Scc9 60 Ssic1 Psl1 Skts4 Skts2 Mom1 Pas1 Tli1 Pctr1 Tlsm1 Liver 70 Gct1 Skts12 Sluc8 Pctr2 Pctm Rvil1 Myc Fv1 80 Hcf2 Scc7 Hcs7 Ccs2 Pas8 90 Ril3 Skts8 P53-dependent Hcs4 Skts13 Scc3

  13. The Circadian Clock Clock genes and cancer? Female shift workers have increased Risk of breast and/or colon cancer Mouse knockouts of Per2 Have increased colon tumors and lymphoma A polymorphism in human PER3 is Associated with breast cancer Fu and Lee, Nature Reviews Cancer, 2003

  14. Control of the Mammalian Circadian Clock Ko, C. H. et al. Hum. Mol. Genet. 2006 15:R271-277R; doi:10.1093/hmg/ddl207

  15. NETWORK ANALYSIS OF HUMAN BREAST CANCER “GOOD PROGNOSIS” Breast cancer Van’t Veer et al, 2002

  16. Aurora-A cytokinesis UBE2T (Fanc) Never-in mitosis Gene a Blooms Mitotic spindle protein Mitotic spindle checkpoint CyclinB PER3 Spc25 Kinetochore protein Anaphase spindle Elongation 1 Mitotic-specific Ubiquitin-conjugating Aurora-B

  17. Chd5 Bagchi et al Cell 2007 Per3 Tumor suppressor genes on human 1p36 (mouse chr.4) Kif1b- Schlisio et al Genes Dev. 2008 Per3

  18. 1.0 5 10 15 20 0 ALL PATIENTS N= 413 0.8 122 291 Disease Free Survival 0.6 PER3 LOW PER3 NORMAL/HIGH 0.4 p= 0.0009 0.2 0.0 39% RECURRENCE 27% RECURRENCE Time (Years) P=0.013 69 ± 3 vs. 56 ± 5 DFS at 10 years ± SE (%) LOW EXPRESSION OF PER3 IS ASSOCIATED WITH POOR PROGNOSIS Van de Vijver et al, NEJM 2002 Chin et al Cancer Cell 2006

  19. 1.0 1.0 0.8 0.8 Probability of Disease Free Survival 0.6 0.6 Probability of Disease Free Survival 0.4 p= 0.9 0.4 0.2 p= 0.0003 0.2 0.0 5 10 15 20 0 Time (Years) 0.0 5 10 15 20 0 56 ± 5 vs. 57 ± 6 Time (Years) 74 ± 3 vs. 54 ± 5 BUT ONLY IN ER-POSITIVE TUMORS ER- ER+

  20. 40 35 30 DMBA gavage Breast cancer incidence (%) 25 20 A 15 10 36% p= 0.005 5 0 WT (n=17) Het (n=33) Null (n=28) 12% Genotype 0% B MMTV-neu per3 1.0 0.8 0.6 Probability of Tumor Free Survival p= 0.003 0.4 0.2 0.0 5 10 15 20 25 0 Time (Months) Per3 null mice are susceptible to breast cancer

  21. Conclusions PER3 is a tumor suppressor gene on 1p36 Deletion of human PER3 is associated with increased Risk of recurrence in ER positive tumors Loss of Per3 has a causal effect in increasing breast cancer in mice. Make sure you get plenty of sleep…

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