The expression of drug resistance gene products during the progression of human prostate cancer

• Published in: Clinical cancer research Vol. 4; no. 6; pp. 1393 - 1403
• Main Authors: SULLIVAN, G. F, AMENTA, P. S, VILLANUEVA, J. D, ALVAREZ, C. J, YANG, J.-M, HAIT, W. N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.06.1998
• Subjects: ATP-Binding Cassette Transporters - analysis; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette, Sub-Family B, Member 1 - analysis; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis; Biological and medical sciences; Disease Progression; DNA Topoisomerases, Type II - analysis; DNA Topoisomerases, Type II - biosynthesis; Drug Resistance, Multiple; Glutathione Transferase - analysis; Glutathione Transferase - biosynthesis; Humans; Immunohistochemistry; Isoenzymes - analysis; Isoenzymes - biosynthesis; Male; Medical sciences; Multidrug Resistance-Associated Proteins; Neoplasm Staging; Nephrology. Urinary tract diseases; Odds Ratio; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - surgery; Proto-Oncogene Proteins c-bcl-2 - analysis; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Tumor Suppressor Protein p53 - analysis; Tumor Suppressor Protein p53 - biosynthesis; Tumors of the urinary system; Urinary tract. Prostate gland; Human; DNA topoisomerase (ATP-hydrolysing); Urinary system disease; Prostate disease; Enzyme; Gene product; Transferases; Tumoral tissue; P Glycoprotein; Malignant tumor; Gene expression; Isomerases; TP53 Gene; Glutathione transferase; C-Onc gene; Multiple resistance; Tumor progression; Advanced stage; Male genital diseases; Prostate; Negative therapeutic reaction; Tumor suppressor gene
• ISSN: 1078-0432; 1557-3265

Prostate cancer progresses from a localized disease to a widely disseminated malignancy. Each step along this progression pathway involves multiple genetic alterations that impart a survival advantage to the tumor cell over its normal counterparts and may confer resistance to therapy. Because metastatic prostate cancer is one of the most therapy-resistant human neoplasms, we studied the expression of certain molecular determinants of drug resistance in the context of tumor progression. Paraffin-embedded formalin-fixed resected prostates were chosen based on Gleason grade and surgical stage. Immunohistochemistry was used to detect the expression of multidrug resistance protein (MRP), topoisomerase II alpha, p53, glutathione S-transferase pi, Bcl-2, and P-glycoprotein in these specimens. We found that all of the proteins were expressed in resected prostate except for P-glycoprotein. The expression of MRP, topoisomerase II alpha, p53, and Bcl-2 increased with the Gleason grade. In addition, the expression of MRP, topoisomerase II alpha, and p53 increased with the surgical stage. In contrast, the glutathione S-transferase pi and Bcl-2 expression decreased with the increasing surgical stage. Stage was the strongest indicator of protein expression. These results suggest that drug resistance gene products are expressed in prostate cancer at the time of surgical resection. Thus, although the emergence of the "pan-resistance" phenotype in prostate cancer may partly be a function of the selection pressure exerted by therapeutic interventions, certain determinants of chemoresistance may be caused by genetic changes accompanying tumorigenesis.