The Molecular Profile of Prostate Tumors in Smokers

Basic Sciences

Investigators

Abstract

SPECIFIC AIM:Identify messenger RNA and microRNA gene expression profiles that are uniquely associated with prostate cancer in smokers.There is strong evidence that tobacco smoking promotes prostate cancer progression. Based on pathology, poorly differentiated and invasive tumors are more common among smokers than nonsmokers. Tobacco smoking is associated with the occurrence of extraprostatic prostate cancer. The risk of extraprostatic disease is greatest for current smokers and increases with increasing cumulative pack-years smoked. An increased risk remains for former smokers. The relative risk of fatal prostate cancer for current smokers, when compared with never smokers, has been estimated to be about 1.3 to 2, but is greater at a younger age and for heavy smokers. There is little evidence that smoking initiates prostate cancer, because most epidemiological studies did not find an association between smoking and the risk of developing the disease. Hence, an active ingredient in tobacco smoke appears to induce changes that turn a local disease into a metastatic disease. These changes depend largely on the continuous supply of this agent because most of the smoking effect disappears after smoking cessation. We will study the messenger and microRNA expression profile in prostate tumors from current, past, and never smokers to establish molecular profiles that distinguish: 1) prostate cancer in current smokers from prostate cancer in never smokers, and 2) prostate cancer in current smokers from prostate cancer in past smokers.Recent data suggest that nicotine has tumor promoting properties in human lung epithelial cells. We set up a cell culture model of human prostate epithelial cells to study the effects of nicotine in prostate carcinogenesis. Initially, we will study the effects of nicotine in immortalized RWPE-1 human prostate cells, and in three prostate cancer cell lines, 22RV1, PC-3, and LNCaP. RWPE-1 cells are HPV-18 immortalized prostate epithelial cells isolated from a normal prostate. We will also test the hypothesis that nicotine causes a distinct gene expression profile in prostate tumors. The first objective is to identify a nicotine-associated gene expression signature in cultured, nicotine-exposed prostate epithelial cells. As the second step, we will compare this gene expression signature with the gene expression profile of prostate tumors from active smokers. If a nicotine-related gene expression signature can be identified in tumors from active smokers, we will test if the signature is a predictor of cancer progression and poor outcome. We will use the RWPE-1, 22RV1, and LNCaP cells to identify a nicotine-induced gene expression profile in human prostate cells. Human prostate tumors from patients with a known smoking status have been obtained the NCI Prostate from our Maryland prostate cancer study, and from the CPCTR.