Core B will provide 3 primary functions to the Program Project. First, Core B will provide research specimens to the investigators and assist with identification, immunostaining and image analysis. Paraffin-embedded sections will be provided from original tumors or tissue microarrays and used to 1) confirm tissue histology using routine H&E;2) analyze apoptosis using ACINUS, proliferation using MIB-1 detection of Ki-67 or BrdU incorporation and androgen receptor using monoclonal antibodies by standard, descriptive immunohistochemistry and quantitative analysis using visual scoring and/or automated image analysis;and 3) identify and quantify steroid receptor co-regulators, androgen metabolism enzymes, androgen-regulated gene products (PSA, Nkx3.1, a-tubulin, translation elongation factor 1a, non-neuronal enolase, tomoregulin, thioredoxin reducatase 1, Mxi-1 and human kallikrein 2), general transcription factors, growth factors and their receptors and stem cell and angiogenesis biomarkers using immunohistochemistry and image analysis. Second, Core B will be responsible for storage, processing and sectioning of clinical (frozen, archival and TMAs) and prostate cancer xenograft (CWR22) research specimens. Core personnel will procure, process and store clinical specimens of castration-recurrent prostate cancer obtained from men with advanced prostate cancer who present with urinary retention due to local recurrence. Research specimens will be used to construct tissue microarrays or laser capture microdissected for biochemical measurements of tissue androgens. Lastly, Core B will provide expert biostatistical (Dr. Wilding) and genitourinary pathological service (Dr. Alexiev) to the Program Project. Drs. Mohler and Smith will co-direct the facility and supervise the activities of individuals who already possess high levels of expertise and currently perform these functions for the Program Project. Drs. Wilding and Alexiev will lead the efforts to integrate biostatistical and pathological expertise into Core B and the 3 projects. The high level of function of Core B is demonstrated best by Core B's publication of 8 methods papers. Core B continues to develop new methods for more accurate measurement of protein expression (4 publications) and remains a leader in the use of TMAs for CaP research (2 publications). Core B has performed services that have resulted in manuscripts published, in press and submitted for Project 1 (20), Project 2 (8) and Project 3 (8). Core B also facilitates interaction among the Projects;12 of 23 publications involved more than 1 Project.

Public Health Relevance

Core B will continue to provide a high level of pathological, technical and biostatistical expertise to the Program Project to assist with management of research specimens, identification of histological sections, immunostaining and quantifying proteins of interest, and data analysis and presentation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077739-15
Application #
8650266
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
15
Fiscal Year
2014
Total Cost
$191,951
Indirect Cost
$33,755
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Mohler, James L (2014) Concept and viability of androgen annihilation for advanced prostate cancer. Cancer 120:2628-37
Titus, Mark A; Li, Yun; Kozyreva, Olga G et al. (2014) 5*-reductase type 3 enzyme in benign and malignant prostate. Prostate 74:235-49
Wilson, Elizabeth M (2014) More evidence intratumoral DHT synthesis drives castration-resistant prostate cancer. Asian J Androl 16:99-100
Kim, Won; Zhang, Li; Wilton, John H et al. (2014) Sequential use of the androgen synthesis inhibitors ketoconazole and abiraterone acetate in castration-resistant prostate cancer and the predictive value of circulating androgens. Clin Cancer Res 20:6269-76
Tan, Jiann-an; Bai, Suxia; Grossman, Gail et al. (2014) Mechanism of androgen receptor corepression by CK*BP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer. Mol Cell Endocrinol 382:302-13
Su, Shifeng; Minges, John T; Grossman, Gail et al. (2013) Proto-oncogene activity of melanoma antigen-A11 (MAGE-A11) regulates retinoblastoma-related p107 and E2F1 proteins. J Biol Chem 288:24809-24
James, Smitha R; Cedeno, Carlos D; Sharma, Ashok et al. (2013) DNA methylation and nucleosome occupancy regulate the cancer germline antigen gene MAGEA11. Epigenetics 8:849-63
Fiandalo, Michael V; Wu, Wenjie; Mohler, James L (2013) The role of intracrine androgen metabolism, androgen receptor and apoptosis in the survival and recurrence of prostate cancer during androgen deprivation therapy. Curr Drug Targets 14:420-40
Chhipa, Rishi Raj; Halim, Danny; Cheng, Jinrong et al. (2013) The direct inhibitory effect of dutasteride or finasteride on androgen receptor activity is cell line specific. Prostate 73:1483-94
Wu, Yue; Godoy, Alejandro; Azzouni, Faris et al. (2013) Prostate cancer cells differ in testosterone accumulation, dihydrotestosterone conversion, and androgen receptor signaling response to steroid 5*-reductase inhibitors. Prostate 73:1470-82

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