ANDROGEN RECEPTORS IN CANCEROUS PROSTATIC TISSUE

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Cancer of the prostate is the second most common cancer in men and the third leading cancer killer. The etiology of the disease is unknown; however, it is absent in castrated individuals, and many tumors retain the property of androgen dependence similar to normal differentiated prostate tissue. It is clear that the greatest progress in understanding steroid hormone action in tumors is through understanding better the properties and physiology of specific steroid receptor proteins. Therefore, there is a need for a more reliable and specific means for studying androgen receptors in tumor tissue. An antibody to the receptor molecule would provide a useful probe for studying the androgen receptor properties in cancer tissue. During the last granting period, we developed the necessary techniques for purifying the androgen receptor from Dunning prostatic tumor. These techniques included both differential binding to DNA-Sepharose and testosterone-affinity chromatography. Furthermore, we characterized the receptor with respect to a number of its physicochemical and steroid-binding properties. We demonstrated three forms of the receptor: a 9.1S nontransformed receptor which does not bind to DNA, a 7.7S receptor-ribonucleoprotein complex and a 4.4S transformed receptor which binds to DNA. The 4.4S receptor appears to be a 120,000 dalton monomer which binds both androgenic steroids and polynucleotides. The other forms of the receptor appear to be composed of the monomer together with other receptor-associated proteins or ribonucleoproteins. In the current proposal we plan to purify each of these receptor species and develop monoclonal antibodies to both the monomer subunit and the receptor-associated proteins. By using these antibodies, we will 1) map out the steroid- and nucleotide-binding domains on the receptor monomer with respect to the N-terminal amino acid, 2) characterize the putative nonsteroid binding proteins associated with the 9.1S receptor, 3) characterize the ribonucleoprotein associated with the 7.7S receptor and 4) determine if these receptor-associated proteins play any physiological role in regulating androgen receptors in target tissues. Antibody probes to the androgen receptor will allow further physicochemical characterization of the protein in androgen regulated prostatic cancer tissues. The long range objective of our laboratory is to be able to use these antibodies to quantitate androgen receptors and determine their mechanism of androgen action in cancerous prostate. This would be a new diagnostic tool for evaluating potential treatment protocols in arresting this disease.