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HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES

HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES. Richard G. Pestell, MD, PhD Kimmel Cancer Center Jefferson University Hospital. Major Genetic Defects in Breast Cancer. Major Genetic Defects in Breast Cancer. Sex Hormone Regulation of Growth Factor Systems in Breast Cancer.

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HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES

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  1. HEREDITARY BREAST CANCER IN DEVELOPING COUNTRIES Richard G. Pestell, MD, PhD Kimmel Cancer Center Jefferson University Hospital

  2. Major Genetic Defects in Breast Cancer

  3. Major Genetic Defects in Breast Cancer

  4. Sex Hormone Regulation of Growth Factor Systems in Breast Cancer

  5. Genetic Alteration of Mammary Epithelial Cells - Progression of Breast Cancer Carcinoma in Situ Mutations in Growth Factor and Sex Steroid pathways governing the cell cycle C-ERBB2 C-MYC CCDN1 CDKN2 RB-1 Mutations in Cell Death Pathways TP53 Overall Chromosomal Instability Metastatic Cancer Further phenotypic alterations in cell cycle Further phenotypic alterations in cell death and response to therapy Phenotypic changes in growth factor secretion governing angiogenesis and metastatic spread Mutations in pathways governing invasion CDH1 Defects in mismatch repair of DNA Hyperplasia Overstimulation of cell cycle and suppression of apoptosis by Estrogen Progesterone Growth Factors Immortalization of cells by expression of Telomerase Predisposing genetic risk Mutations affecting DNA repair and apoptosis in BRCA-1 BRCA-2 TP53 PTEN

  6. BRCA1 Protein Function • Regulation of cell cycle progression • DNA repair: “caretaker” function • Programmed cell death (apoptosis) • Regulation of gene transcription

  7. BRCA1 Protein: Structural Features -1863 aa -220 kDa nuclear phosphoprotein -N-terminal RING domain (aa 20-64) interacts with BARD1 ubiquitin ligase activity -C-terminal TAD (last 95-100 aa) mediates transactivation BRCT repeats

  8. Role in DNA Damage Response Specialized DNA repair processes -Homology-directed repair -Transcription coupled repair -Mismatch repair -Nucleotide excision repair -Fanconi repair DNA damage signaling: ATM, ATR, Chk2 DNA damage responsive cell cycle checkpoints: S & G2/M

  9. Regulation of BRCA1 Expression Increased Expression -cancer chemoprevention – indole-3-carbinol, genistein -mammary epithelial cell differentiation -cell cycle -  in late G1, early S-phase Decreased Expression -30-40% sporadic breast cancers: promoter methylation -ethanol -polycyclic aromatic hydrocarbons – B(a)P, BPDE -persistent organochlorines (PCBs) -p53 activation -Id4 (bHLH transcriptional regulator)

  10. BRCA1 Regulated Transcriptional Pathways -interacts w/ basal transcription factor (RNA helicase A) -C-terminus: chromatin unfolding activity (COBRA1) -associates w/ Brg1 (SWI/SNF chromatin remodelling) -stimulates Gadd45, p21WAF1, p27Kip1 expression -coactivator for p53 -inhibits c-Myc activity and TERT expression -interacts with STAT1–interferon -mediated transcription -regulates nuclear receptor function

  11. BRCA1 transcriptional regulation

  12. BRCA1-interacting proteins

  13. BRCA1-transcription repression

  14. BRCA1 represses ERa Science, V284, p1354,1999

  15. BRCA1 Domains for ERInhibition LXCXE RING NLS Rad51 TAD 220 Du-145 T47D wt BRCA1 1 500 1000 1500 1863 200 5677-InsA 1 1852 120 Bam H1 1 1313 Luciferase Activity (% of pcDNA3 Vector Control) 100 Kpn 1 1 771 80 EcoR 1 1 302 60 185delAG 1 38 40 T300G 61 Cys/Gly 1 1863 20 RXRXH 1 1863 0 358 RXRXH 5382InsC RXRXH T300G 1 1755 Kpn 1 C5365G EcoR 1 pcDNA3 5382InsC Bam H1 185delAG 5677-InsA wt BRCA1 C5365G 1 1749Pro/Arg 1863

  16. ER Binds Cyclin D1 A B DBD LBD Western IP WB ER + + - - AF-1 AF-2 E2 ER ER *** HE74 HE74 F F 1-530 1-530 E/F E/F 1-378 1-378 1-282 1-282 Cancer Res, Wang et al 2005

  17. GST-Cyclin D1 Binds to ER DBD LBD ER GST D1 GST AF-1 AF-2 ER 1 595 *** HE74 1 595 HE19C 179 595 F 1 554 1-530 1 530 E/F 1 388 1-282 1 282 Cancer Res, Wang et al 2005

  18. Cyclin D1 Overcomes Repression by BRCA1 BRCA1 D1 Co-activator D1 Co-activator BRCA1 N N C C C N ER ER ER Co-activator BRCA1

  19. Hereditary Breast Cancer in Developing Countries -Relative contribution to breast cancer ? -Common or distinct mutations ? -Role of polymorphisms in onset,progression and therapy (cyclin D1,Bcl2, other) ? -Role in screening- cultural sensitivity vs treatment triage -Economic priorities ? -Global collaboration in molecular epidemiology ?

  20. BRCA1 Inhibits Estrogen-Induced Genes Serum-Free DMEM DMEM+10%FCS Serum-Free DMEM DMEM+10%FCS - + - + E2 (10-6M) - - + + wtBRCA1 - + - + E2 (10-6M) - - + + wtBRCA1 pS2 pS2 Cathepsin-D Cathepsin-D -Actin -Actin

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