Abstract 4973: The role of cholesteryl esters in progression and racial disparity of prostate cancer

Background Prostate cancer (PCa) is featured by uncertainty of future outcomes at the time of diagnosis, development of castration resistant prostate cancer (CRPC), and racial disparity in morbidity and mortality, which is especially prominent between African American (AA) and Caucasian American (CA). This study is aimed to investigate whether accumulation of cholesteryl esters (CE) in PCa is a key biological process that determines progression potential, and serves as a common mechanism underlying these features. Methods The methods used in this study include: 1) ESI/MS-MS on 47 fresh-frozen prostatic tissues for global lipid profiling; 2) Real-time PCR on 16 fresh-frozen prostatic tissues for the expression level of genes related to the pathogenesis of prostate cancer and metabolism of cholesteryl esters; and 3) immunohistochemistry on 165 formalin-fixed and paraffin embedded prostatic tissues for the expression level of ACAT1 and LAL. Results We found that 1) prostatic concentration of total lipids was significantly higher in PCa than benign prostatic tissues (BPT), with a PCa to BPT (P/B) ratio of 2.3, p = 0.013; 2) when total lipids were stratified into groups of neutral lipids and polar lipids, only neutral lipids are significantly higher in PCa than BPT (P/B ratio: 3.1, p = 0.02); 3) after neutral lipids were further stratified into class of triglycerides, diglycerides, free fatty acids (FFA) and CEs, total CEs are most sensitive in differentiation of PCa from BPT (P/B ratio: 5.8, p = 0.025); 4) 17 out of 31 prostatic individual CE species are significantly higher in PCa than in BPT all the studied populations; and 5) intriguingly, 14 of these 17 prostatic CE individual species remain significantly different between PCa and BPT in AA population, whereas only 3 of them remain significantly different between PCa and BPT in the CA population. The real-time PCR results indicated that the expression levels of genes Pten, LIPA, and ABCA1 are obviously lower in high grade than in low grade PCa (not obviously for ACAT1). The expression levels of proteins ACAT1 and LAL (LIPA gene product) are reversely correlated with the progression of PCa: in prostate cancer, ACAT1 is highly expressed, but LAL is not expressed. In contrary, in benign ACAT1 is not expressed, but LAL is highly expressed. Such a reverse correlation is especially prominent in AA than CA population. Conclusion and Significance Accumulation of cholesterol esters correlates with the progression and racial disparity of PCa. Down regulation of LIPA gene and its product LAL could play major role in CE accumulation. Thus prostatic CE and its individual species could serve as racially specific biomarkers in diagnosis and in differentiation of indolent from aggressive cases of PCa, and LAL could be potential therapeutic targets for treatment of advanced prostate cancer, including castration resistant prostate cancer. Citation Format: Xinchun Zhou, Timera Brown, Janice Lage, Jinghe Mao. The role of cholesteryl esters in progression and racial disparity of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4973.