Structural Requirements for the in vitro Transformation of Syrian Hamster Embryo Cells by Stilbene Estrogens and Triphenylethylene‐Type Antiestrogens

The mechanisms of estrogen-induced cancer are still a matter of debate. Previous studies with stilbene estrogens and steroidal estrogens have shown that the in vitro transformation of primary Syrian hamster embryo (SHE) fibroblasts is a good experimental system for discriminating hormonal from nonhormonal events. We have now extended these studies to the triphenylethylene-type antiestrogens tamoxifen (TAM), 3-hydroxy-TAM, 4-hydroxy-TAM and 3,4-dihydroxy-TAM. Furthermore, a structural isomer of diethylstilbestrol (DES) with the hydroxy groups shifted into the meta-positions (3,3′-DES) was included. Our data clearly show that TAM and 4-hydroxy-TAM give rise to morphologic and neoplastic transformation of SHE cells in culture. In contrast, neither 3-hydroxy-TAM nor 3,3′-DES led to a significant transformation, in spite of the fact that both compounds are hormonally active. These results support the notion that nonhormonal events are essential for SHE cell transformation and suggest certain structural features to be necessary for the transforming capability. The putative carcinogenicity of TAM and 4-hydroxy-TAM but not of 3-hydroxy-TAM, as implied by these in vitro transformation studies, is corroborated by recent reports on ovarian and Leydig cell tumors in mice and hepatocellular carcinomas in rats.