Prostate cancer is the most common lethal tumor among US males yet little is known about its causative mechanisms. This study proposes to examine how glycosylation of sex hormone binding globulin (SHBG) affects steroid hormone signaling in prostate cancer. We will define the impact of SHBG glycosylation, including the D327N SHBG polymorphism, on steroid hormone associated prostate cancer risk and disparity in African and Caucasian Americans. Protein glycosylation is critical for interaction of prostate cells with its environment. We will evaluate how glycosylation of SHBG affect the distribution of the protein between plasma and tissue and how this affects disease development. The quantification of the SHBG glycoforms will be achieved by novel LC-MS assays. In addition, we will comprehensively summarize the impact of polymorphisms on N-glycosylation in the human proteome. Our hypothesis is that prostate cancer risk and progression are related to the variability in the glycosylation of SHBG. Our objective is to perform quantitative mass spectrometric assays of SHBG glycosylation in conjunction with measurement of steroid hormones. We will select men for phenotypic characterization by genotyping of a case control population with 50% African American representation. In addition, we will genotype a case series for which both serum and tissue are available. Steroid hormones will be measured by GC-MS. We will analyze the SHBG glycoforms and steroid hormones at the tissue level and in the circulation. The study is expected to fill important gaps in our understanding of prostate cancer etiology and progression. The analysis of SHBG glycoforms will provide new information on the biological factors underlying prostate carcinogenesis. The results are expected to improve prostate cancer prevention, detection and intervention strategies.

Public Health Relevance

This research is important because a comparative analysis of SHBG glycosylation and steroid hormones in prostate cancer, especially in African American men, has not been previously undertaken. We are proposing the first large scale examination of SHBG site occupancy in prostate cancer and health disparity of the disease. The newly established informatic resources and methods are expected to stimulate novel cancer prevention and health disparity studies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA171146-02
Application #
8547797
Study Section
Special Emphasis Panel (ZRG1-OBT-A (55))
Program Officer
Sathyamoorthy, Neeraja
Project Start
2012-09-19
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$287,294
Indirect Cost
$51,132
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Sanda, Miloslav; Zhang, Lihua; Edwards, Nathan J et al. (2017) Site-specific analysis of changes in the glycosylation of proteins in liver cirrhosis using data-independent workflow with soft fragmentation. Anal Bioanal Chem 409:619-627
Wang, Mengjun; Sanda, Miloslav; Comunale, Mary Ann et al. (2017) Changes in the Glycosylation of Kininogen and the Development of a Kininogen-Based Algorithm for the Early Detection of HCC. Cancer Epidemiol Biomarkers Prev 26:795-803
Kozlik, Petr; Goldman, Radoslav; Sanda, Miloslav (2017) Study of structure-dependent chromatographic behavior of glycopeptides using reversed phase nanoLC. Electrophoresis 38:2193-2199
Flowers, Sarah A; Zhou, Xin; Wu, Jing et al. (2016) Expression of the extracellular sulfatase SULF2 is associated with squamous cell carcinoma of the head and neck. Oncotarget 7:43177-43187
Sanda, Miloslav; Goldman, Radoslav (2016) Data Independent Analysis of IgG Glycoforms in Samples of Unfractionated Human Plasma. Anal Chem 88:10118-10125
Goldman, Radoslav; Sanda, Miloslav (2015) Targeted methods for quantitative analysis of protein glycosylation. Proteomics Clin Appl 9:17-32
Yuan, Wei; Sanda, Miloslav; Wu, Jing et al. (2015) Quantitative analysis of immunoglobulin subclasses and subclass specific glycosylation by LC-MS-MRM in liver disease. J Proteomics 116:24-33
Singer, Mark S; Phillips, Joanna J; Lemjabbar-Alaoui, Hassan et al. (2015) SULF2, a heparan sulfate endosulfatase, is present in the blood of healthy individuals and increases in cirrhosis. Clin Chim Acta 440:72-8
Wallace, Tiffany A; Downey, Ronan F; Seufert, Caleb J et al. (2014) Elevated HERV-K mRNA expression in PBMC is associated with a prostate cancer diagnosis particularly in older men and smokers. Carcinogenesis 35:2074-83
Benicky, Julius; Sanda, Miloslav; Pompach, Petr et al. (2014) Quantification of fucosylated hemopexin and complement factor H in plasma of patients with liver disease. Anal Chem 86:10716-23

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