Abstract
Prostate cancer remains a major public health problem and the second leading cause of cancer-related deaths in men in the United States. The present study aims to understand the molecular pathway(s) of prostate cancer which is essential for early detection and treatment. Dorsolateral prostate from 20 week transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, which spontaneously develops prostate cancer and recapitulates human disease and age-matched non-transgenic littermates were utilized for microarray analysis. Mouse genome network and pathway analyses were mapped to the human genome using the Ingenuity Pathway Analysis (IPA) database for annotation, visualization, and integrated discovery. In total, 136 differentially expressed genes, including 32 downregulated genes and 104 upregulated genes were identified in the dorsolateral prostate of TRAMP, compared to non-transgenic mice. A subset of differentially expressed genes were validated by qRT-PCR. Alignment with human genome database identified 18 different classes of proteins, among these, 36% were connected to the nucleic acid binding, including ribosomal proteins, which play important role in protein synthesis—the most enriched pathway in the development of prostate cancer. Furthermore, the results suggest deregulation of signaling molecules (9%) and enzyme modulators (8%) affect various pathways. An imbalance in other protein classes, including transporter proteins (7%), hydrolases (6%), oxidoreductases, and cytoskeleton proteins (5%), contribute to cancer progression. Our study evaluated the underlying pathways and its connection to human prostate cancer, which may further help assess the risk of disease development and progression and identify potential targets for therapeutic intervention.
Highlights
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States (Cronin et al, 2018; Negoita et al, 2018)
20 week dorsolateral prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse consists of poorly differentiated prostatic intraepithelial neoplasia (PIN) characterized by profound cribriform structures and numerous apoptotic bodies, invasive glands accompanied by marked thickening, remodeling, and hypercellularity of the fibromuscular stroma
Malignant lesions were detected in 40–50% abundance in the dorsolateral prostates of TRAMP mouse consisting of well-differentiated adenocarcinoma (30– 40%), along with moderately-differentiated cancer (5–10%) and, infrequently, poorly-differentiated adenocarcinoma (
Summary
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States (Cronin et al, 2018; Negoita et al, 2018). Understanding the molecular pathways of prostate cancer is essential for early detection and treatment. Elucidation of molecular pathways leading to prostate cancer development and progression is difficult to attain in patients, as these studies may require decades of observation. Such studies are hindered by the need for obtaining repeat biopsies from the patients under surveillance. It is advantageous to evaluate molecular pathways of prostate cancer development and progression in animal models that recapitulate human disease. Some established animal models include tumor suppressor knockout PTEN mouse (Wang et al, 2003); gain of function model such as the c-myc mouse (Ellwood-Yen et al, 2003); and various
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