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INFLAMMATION AND BREAST CANCER

INFLAMMATION AND BREAST CANCER. Stefan Ambs Breast and Prostate Unit Laboratory of Human Carcinogenesis. EPIDEMIOLOGY. NSAIDs protect against breast cancer Meta-analysis*: RR 0.82; 95% CI 0.75 to 0.89 NSAID or conditions of self-selected use?

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INFLAMMATION AND BREAST CANCER

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  1. INFLAMMATION AND BREAST CANCER Stefan Ambs Breast and Prostate Unit Laboratory of Human Carcinogenesis

  2. EPIDEMIOLOGY • NSAIDs protect against breast cancer • Meta-analysis*: RR 0.82; 95% CI 0.75 to 0.89 • NSAID or conditions of self-selected use? • Antibiotics use is associated with increased breast cancer risk • Use of antibiotics or indications for them? • Women’s Health Study (10-year trial) • 100 mg aspirin every other day does not protect** * BJC 84, 1188-1192, 2001 ** JAMA 294, 47-55, 2005

  3. ANIMAL MODELS • Inhibition of mammary carcinogenesis • NSAID • NOS2 KO • Induction of mammary carcinogenesis • COX2 over-expression • Pro-inflammatory (colitogenic) T cells • Pathogenic gut bacteria • Oxidative stress

  4. TUMOR MARKERS • Inflammation markers • Association with angiogenesis, histological grade, outcome • Tumor-infiltrating macrophages • Cyclooxygenase-2 • Nitric oxide synthase-2 • Inflammation or wound healing response? • Inflammatory breast cancer • Most aggressive form of breast cancer • “Inflammatory” is a misnomer

  5. Hypothesis:Inflammation activates the Akt pathway in breast tumors • Breast tumors • Markers of inflammation: NOS2, COX2, macrophages (CD68) • Akt pathway activation: Phosphorylated Akt, BAD, caspase-9 • Cell culture

  6. IHC ANALYSIS OF 248 BREAST TUMORS NOS2 COX2

  7. AKT PHOSPHORYLATION Thr308 Ser473

  8. STATISTICAL ANALYSIS Spearman rank correlation Association in multivariate analysis (logistic regression model)

  9. NO INDUCES AKT PHOSPHORYLATION

  10. PGE2 INDUCES AKT PHOSPHORYLATION

  11. ANA-1 MACROPHAGES INDUCE AKT PHOSPHORYLATION

  12. AKT ACTIVATION INDUCES COX2

  13. CONCLUSION Int. J. Cancer 120: 796-805, 2006

  14. Hypothesis:NOS2 expression predicts poor outcome in breast cancer • Survival analysis (248 patients) • Kaplan-Meier • Multivariate Cox regression • Gene expression profiling (32 patients) • High versus low NOS2

  15. ASSOCIATION WITH TUMOR MARKERS * Adjusted for TNM stage and neoadjuvant therapy

  16. NOS2 EXPRESSION PREDICTS POOR SURVIVAL IN ERα-NEGATIVE BREAST CANCER Cumulative Survival P = 0.001 Low NOS2 1.00 0.75 0.50 High NOS2 0.25 0 0 1000 2000 3000 4000 5000 Survival Time (days)

  17. MULTIVARIATE SURVIVAL ANALYSIS Adjusted* Cox regression analysis * Covariates: age, race, TNM stage, histological grade, tumor p53 status

  18. GENE EXPRESSION PROFILING Breast tumors • Low NOS2 (IHC), n = 17 • High NOS2 (IHC), n = 15 • LCM, Affymetrix Gene Chip HG-U133A Results • Gene signature in ER-negative tumors (n = 17) • About 50 genes at low false discovery rate • No identifiable NOS2-related gene signature in ER-positive tumors (n = 15)

  19. POOR OUTCOME SIGNATURE OF NOS2

  20. CONCLUSION • NOS2 expression is associated with poor outcome among patients with ER-negative tumors • NOS2 expression is associated with a distinct gene expression profile in these tumors • Basal-like subtype

  21. FUTURE COURSE NO • MCF-7 • T47D • MDA-MB-231 • MDA-MB-468 ER-positive ER-negative • Expression • Basal-like markers • Interleukin-8 • S100A8 • etc.

  22. ACKNOWLEDGEMENTS • Laboratory of Human Carcinogenesis, NCI • Sharon Glynn, Robyn Prueitt, Tiffany Howe, Brenda Boersma, Candice Pfiester • Radiation Biology Branch, NCI • Douglas Thomas, Lisa Ridnour, David Wink • South Carolina College of Pharmacy • Lei Ying, Lorne Hofseth • Advanced Biomedical Computing Center, NCI • Ming Yi, Bob Stephens

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