17?-Estradiol, diethylstilbestrol, tamoxifen, toremifene and ICI 164,384 induce morphological transformation and aneuploidy in cultured Syrian hamster embryo cells

Abstract

Many estrogenic chemicals are carcinogenic in different species. Carcinogenicity of the synthetic estrogen diethylstilbestrol (DES) is demonstrated in humans and in rodents (IARC, 1979). The natural steroidal estrogen 17b-estradiol (E 2 ) also exhibits carcinogenic activity in a number of experimental animals (IARC, 1979). The mechanism of carcinogenesis by estrogens has not been fully elucidated, but strong evidence exists to support the hypothesis that estrogens are epigenetic carcinogens acting via a promoting effect related to cellular proliferation mediated by the estrogen receptor (ER) (Sheehan et al., 1982). In contrast, experimental support for another mechanism, related to genotoxicity, has been provided in many reports for estrogen-induced carcinogenesis.DES has been shown to induce genotoxic effects in cultured mammalian cells with exogenous metabolic activation and in cells with possible endogenous activation capacity for DES (Tsutsui et al., 1986). We have studied the cell transforming activity and genotoxicity of DES and E 2 using Syrian hamster embryo (SHE) cells, which do not express measurable levels of the ER (Barrett et al., 1981;Tsutsui et al., 1983Tsutsui et al., , 1986Tsutsui et al., , 1987. The SHE cell transformation assay measures the induction of pre-neoplastic cells by scoring morphologically altered colonies of cells that form 7-8 days after exposure to chemical/physical carcinogens (Tsutsui et al., 1983). Treatment of SHE cells with DES or E 2 induces cellular transformation without measurable gene mutations, unscheduled DNA synthesis (UDS) or structural chromosomal aberrations (Barrett et al., 1981;Tsutsui et al., 1983Tsutsui et al., , 1987. Under the same conditions, both estrogens induce a specific type of genetic change, i.e., aneuploidy. Chromosome losses and gains are induced (Tsutsui et al., 1983(Tsutsui et al., , 1987, suggesting a non-disjunctional mechanism involved in the transforming activity. However, UDS and gene mutation at the Na 1 /K 1 ATPase locus are elicited when SHE cells are treated with DES in the presence of a rat liver postmitochondrial supernatant metabolic activation system. Enhancement of the transformation frequencies is accompanied with this treatment (Tsutsui et al., 1986). Thus, we have proposed 2 potential mechanisms for estrogen-induced cellular transformation: one does not involve direct DNA damage and the other one is associated with DNA damage. Cellular DNA damage induced by chemicals can be examined by detection of DNA adduct formation through covalent modification of DNA. Liehr et al. (1986) demonstrated the presence of covalent DNA adducts in pre-malignant lesions in the kidneys of Syrian hamsters treated chronically with estrogens using a 32 P-postlabeling assay. In addition, exposure of SHE cells to DES and E 2 leads to covalent DNA adduct formation, corresponding to induction of cellular transformation (Hayashi et al., 1996).The triphenylethylene non-steroidal tamoxifen (TAM), which is a structural analogue of DES (Fig. 1), exerts anti-estro...

Extensive Chromosomal Breaks Are Induced by Tamoxifen and Estrogen in DNA Repair-Deficient Cells

“…Indeed, treatment of wild-type cells with relatively high doses of TAM results in the inhibition of cell proliferation without a detectable increase in the number of chromosomal aberrations (10). To circumvent this problem, we have now studied a panel of DNA repair mutants and exposed these cells for extended periods to TAM, E 2 , or their metabolites at lower doses that are similar to the serum concentrations associated with cancer treatment in humans.…”

Characterization of a cell line established from diethylstilbestrol-induced renal tumors in syrian hamsters

“…By contrast, treatment with DES leads to a marked elevation of the frequency of near diploid and near tetraploid cells in renal tissue (17). Since HKT-1097 cells derive from tumor tissue, it is difficult to ascertain whether the karyotype instability seen in this cell line is a direct consequence of exposure to DES (30) or is a manifestation of the transformed phenotype. Anyway, it is worth noting that chromosome imbalance has been put forward along with regenerative hyperplasia as a major factor contributing to estrogen carcinogenesis in the hamster kidney (16), To our knowledge, there are in the literature only two reports of long-term cell cultures having been established from estrogen-induced SHKT.…”

Role of Estrogen in Alcohol Promotion of Breast Cancer and Prolactinomas

“…The induction of mutations by estrogen or its metabolites has been implicated in carcinogenesis. Aneuploidy and structural chromosomal aberrations are induced by estradiol both in cells in culture and in a target organ of estrogen-induced cancer, the Syrian hamster kidney (Banerjee et al, 1992(Banerjee et al, , 1994aTsutsui et al, 1987Tsutsui et al, , 1990Tsutsui et al, , 1997Tsutsui et al, , 2000. In the same animal model, estradiol induces c-myc gene amplification and microsatellite instability (Hodgson et al, 1998;Li et al, 1999).…”