INDUCTION OF CATHEPSIN-D PROTEIN DURING ESTROGEN CARCINOGENESIS - POSSIBLE ROLE IN ESTROGEN-MEDIATED KIDNEY TUBULAR CELL-DAMAGE

We have proposed that an early step in estrogen carcinogenesis in the hamster kidney is tubular damage followed by reparative cell prolifera tion, This tubular injury is progressive and increases in severity wit h continued estrogen treatment; one pertinent feature is a marked rise in the number of both secondary and tertiary lysosomes, Data presente d herein indicate that cathepsin D, an estrogen-responsive lysosomal p roteolytic enzyme, is increased in the kidney following estrogen treat ment in the hamster, Three isoforms of cathepsin D were detected in es trogen-treated kidneys, 52, 31, and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen treatment, 52-kDa cathepsin D content incr eased 1.4- to 1.6-fold, These changes coincided with a rise in renal e strogen receptor levels during the same estrogen treatment periods, Mo re pronounced rises in cathepsin D levels, 2.7- and 3.5-fold, were see n after 4 and 5 months of estrogen treatment, respectively, A concomit ant, 3.0- to 4.0-fold rise in estrogen receptor content was also obser ved, At 5 months of estradiol or DES treatment, both 27- and 31-kDa is oforms were present in hamster kidneys, in addition to the 52-kDa form , Neither progesterone nor DHT treatment affected the untreated levels of cathepsin D, Interestingly, either concomitant tamoxifen or DHT an d estrogen treatment prevented the rise in cathepsin D and estrogen re ceptor content observed after estrogen treatment alone, Primary estrog en-induced renal tumors and their metastases exhibited markedly elevat ed levels of all three isoforms of cathepsin D, Immunohistochemical an alysis of cathepsin D in kidney sections confirmed the Western blot fi ndings, These data suggest a novel role for estrogen-induced cathepsin D in the hamster kidney during tumorigenesis; that is, mediating rena l tubular damage as a prelude to reparative cell proliferation, thus i nitiating a multi-step estrogen-driven process which leads to renal tu mor formation.