E2F3 in Soft Tissue Sarcoma Development M. Scurr; A Feber; J Shipley; A Fletcher; N Dennis; I Judson; C Cooper.

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Presentation transcript:

E2F3 in Soft Tissue Sarcoma Development M. Scurr; A Feber; J Shipley; A Fletcher; N Dennis; I Judson; C Cooper

Active E2F3 RB E2F3 P P Cyclin D CDK RB Cyclin E, CDK2 G1/S Transition Growth Factors P DNA synthesis (TS,TK,DHFR) Cyclin A

E2F3 Overexpression and Cancer Human Bladder Cancer(Feber et al) E2F3 an oncogene activated by gene amplification and overexpression. E2F3 overexpression correlates with increasing grade and stage Prostate Cancer(Foster et al) E2F3 overexpression an independent variable overall survival (P=.0014) cause specific survival(P=.0004)

Evaluation of Potential Role for E2F3 in STS RB1 mutation/loss in STS ~1/3 of leiomyosarcomas Up to 70% of primary tumours altered RB expression Reports of cyclin D1/Cdk4 overexpression Implicating RB-E2F Axis

STS Tissue Microarrays 165 patients with primary tumour samples and clinical data Tumour Type Patient N o Leiomyosarcoma 118 MFH 97 Synovial Sarcoma 52 Fibrosarcoma 23 TOTAL290

Fibrosarcoma MFH Leiomyosarcoma Monophasic Synovial Sarcoma    

Epithelial cell stainingSpindle cell staining  

E2F3 Nuclear Staining:Total STS TMA

LeiomyosarcomaFibrosarcoma MFHSynovial Sarcoma

Prostate Cancer

Clinical Correlations: E2F3 Staining and Prognostic Variables. Size Stage Grade

Clinical Correlations: E2F3 Staining and Prognostic Variables. Size No significant correlation StageNo significant correlation Grade

Clinical Correlations: E2F3 Staining and Prognostic Variables. Size No significant correlation StageNo significant correlation GradeP<0.001

Clinical Outcomes: Disease Free Survival UNIVARIATE ANALYSIS size stage grade MULTIVARIATE ANALYSIS stage +ve E2F3 nuclear staining HR 1.41 (95% CI ) P=0.148

Clinical Outcomes: Disease Free Survival UNIVARIATE ANALYSIS size stage grade MULTIVARIATE ANALYSIS stage +ve E2F3 nuclear staining HR 1.45 (95% CI ) P=0.1

Clinical Outcomes: Cause Specific Survival UNIVARIATE and MULTIVARIATE ANALYSES size stage grade site

Clinical Outcomes: Cause Specific Survival UNIVARIATE and MULTIVARIATE ANALYSES size stage grade site +ve E2F3 nuclear staining HR 1.57 (95% CI ) P=0.10

Assessment of biological function of E2F3 overexpression in STS

E2F3 in STS Cell Lines HT1080 HTB-88 HTB-114 SKW SS-SY-II BAX FUJI 5637 (+ve control) GAPDH E2F3

E2F3 in STS Cell Lines HT1080 HTB-88 HTB-114 SKW SS-SY-II BAX FUJI 5637 (+ve control) GAPDH E2F3

E2F3 siRNA Transfection: 24 hours E2F3  GAPDH  Si-1 Si-2 Si-3 Si-all Scr-1 Scr-2 Scr-3 Scr-all control 

Biological effect of “knocking down” E2F3 production Si-3 and Scr-3 transfection of HT 1080 Analysis of effect on G1/S transition BrdU Incorporation: Immunofluorescence Microscopy fluorescent activated cell sorting (FACS)

BrdU Incorporation Immunofluorescence Microscopy Si-3 Scr-3

BrdU Incorporation: FACS Si-3: 0 hrsSi-3: 24 hrs post Scr-3: 0 hrsScr-3: 24 hrs post

Conclusions 62% STS samples positive E2F3 nuclear staining LMS/MFH and fibrosarcoma predominantly <20% intensity Synovial sarcoma more intense staining similar pattern to prostate and bladder cancer. +ve Nuclear staining correlates with higher grade Non-significant trend to poorer disease free and cause specific survivals E2F3 knockdown studies demonstrate that inhibition of E2F3 expression inhibits cell cycle progression. E2F3 OVEREXPRESSION HAS A ROLE IN THE MALIGNANT PHENOTYPE IN STS

Acknowledgements Institute of Cancer Research Molecular Carcinogenesis Colin Cooper Andy Feber Sandra Edwards Penny Flohr Toby Roe Jeremy Clark Janet Shipley Anne Fletcher Nening Dennis Cancer Therapeutics Jenny Titley Mike Walton Royal Marsden Hospital Sarcoma Unit Ian Judson Omar Al-Muderis Histopathology Department Cyril Fisher Statistics Roger Ahern University of Liverpool Department of Pathology and Medical Genetics Chris Foster Andy Dodson Supported by: Royal Marsden NHS Trust Charitable Fund Grant Jeannette Pomeraniec Sarcoma Research Fund