Estrogen carcinogenesis in the hamster kidney: a hormone-driven multistep process.

It is proposed that the kidney cytotoxicity or tubular damage and the subsequent regenerative cell proliferation elicited by estrogens after chronic hormone treatment is driven specifically by the intrinsic estrogenic property of these agents. The sequence of events leading to estrogen-induced renal tumorigenesis in the hamster is presented in Figure 2. There are a number of events that occur rapidly and nearly simultaneously. First, there is an alteration in kidney proximal tubule (PCT) cells that is manifested by an elevation in both ER and PR at about 1.5 and 3 months, respectively. This clearly demonstrates an increased responsiveness of the kidney tubule to estrogen. Second, there is a progressive PCT cytotoxicity or cell injury, occurring as early as 1.5 months, which increases in severity with continued estrogen exposure. Initially, when the tubular damage is not severe, the reparative hyperplasia occurs mainly in the mature proximal tubules. Third, with increased severity in renal tubular cell damage, committed epithelial interstitial stem cell populations, shown to be the origin of this tumor, begin to proliferate in an effort to repair the increasing cell damage induced by chronic estrogen treatment. As a consequence of this regenerative cell proliferation, in both mature proximal tubules (limited) and primitive interstitial stem cells, aneuploid cells in both dividing mature and primitive kidney cells are significantly elevated. This view is consistent with the specific estrogen-induced cell proliferation in culture cited earlier. Evidence has recently been provided in our laboratory that suggests that chromosomal instability as a result of nonrandom chromosomal alterations (trisomies, tetrasomies, monosomies) as well as other chromosomal aberrations contribute critically to early events in renal tumorigenesis in the hamster. Moreover, overexpression of protooncogenes and suppressor genes occurs as early as 4 months of estrogen treatment. Therefore, the nongenotoxic estrogen-induced neoplastic transformation in the hamster kidney is suggested to occur in a series of discrete molecular events that is now believed to be primarily hormonally driven and hormonally dependent.