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Nuclear Expression of PTHrP and Outcome in Non-Small Cell Lung Cancer Randolph H. Hastings and Leonard J. Deftos VA

Nuclear Expression of PTHrP and Outcome in Non-Small Cell Lung Cancer Randolph H. Hastings and Leonard J. Deftos VA San Diego Healthcare System Parathyroid Hormone-related Protein (PTHrP) Responsible for hypercalcemia of malignancy Homology with parathyroid hormone 1-34

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Nuclear Expression of PTHrP and Outcome in Non-Small Cell Lung Cancer Randolph H. Hastings and Leonard J. Deftos VA

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  1. Nuclear Expression of PTHrP and Outcome in Non-Small Cell Lung CancerRandolph H. Hastings and Leonard J. DeftosVA San Diego Healthcare System

  2. Parathyroid Hormone-related Protein (PTHrP) • Responsible for hypercalcemia of malignancy • Homology with parathyroid hormone 1-34 • Reproduces the actions of PTH • Acts as a local growth factor • Expressed in all types of lung cancer

  3. P PTHrP Isoforms

  4. P PTHrP Processing

  5. Nuclear Localization of PTHrP • Two nuclear localization sequences • NLS have clusters of basic residues

  6. Nuclear localization is greatest for the PTHrP 1-173 isoform

  7. Nuclear PTHrP in Human Lung Cancer

  8. Nucleolar PTHrP in MV-522 Lung Cancer Cells

  9. Nuclear PTHrP Exerts Intracrine Effects • Intracrine actions alter growth or apoptosis • Intracrine effects may oppose cell surface effects

  10. PTHrP 1-34 and 140-173 protect against apoptosis

  11. PTHrP 1-173 gene transfer sensitizes to apoptosis

  12. TUNEL staining in A549 cells after hydrogen peroxide vector PTHrP 1-87 PTHrP 1-173

  13. Opposing Effects of PTHrP on Apoptosis in Lung Cancer Cells • Paracrine effects protect. • Intracrine effects sensitize.

  14. PTHrP and Cancer • Expressed in many cancers, with and without associated hypercalcemia • Growth factor for many cancer cell lines • Favors bone metastasis in animal models • Associated with improved survival in breast cancer

  15. Hypothesis Nuclear expression of PTHrP and/or expression of PTHrP 1-173 increases survival in patients with non-small cell lung cancer.

  16. Evaluate survival as a function of PTHrP expression • Stain lung cancer sections for PTHrP protein and mRNA for the PTHrP isoforms. • Collect survival, stage, histology, age and gender data from computerized cancer registry • Analyze effect of PTHrP on 12-month survival with a Cox proportional hazards model

  17. Resources • Well established immunohistology laboratory • VA San Diego Cancer Registry (570 NSCLC patients) • UCSD Tumor Registry (1286 NSCLC patients) • UCSD Cancer Center Biostatistics Resource

  18. Opportunities for Collaboration • Pathologist to assist with slide evaluation • Oncologist to discuss clinical relevance, consider future studies

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