Estrogens (natural or synthetic) are regarded as promoters and/or initiators of the carcinogenic processes by triggering multiple genes that could be related to cell proliferation, apoptosis and tumor angiogenesis. As Bcl-2 and Bax genes are key determinants in regulating apoptosis, present study was undertaken to investigate whether ratio of Bcl-2 and Bax level significantly altered during estrogen induced pituitary tumorigenesis in F344 rat, a relevant model for the study of hormonal carcinogenesis. To test this, silastic capsules with or without estrogens [17β-estradiol (carcinogenic) or 17α-estradiol (non-carcinogenic)] were surgically implanted under the skin of rats and kept them for 15 days for pituitary tumor growth. As expected, pituitary wet weight, prolactin mRNA level, PCNA labeling index were significantly elevated in the pituitaries of carcinogenic estrogen exposed rats as compared to 17α-estradiol or untreated rat pituitaries. Moreover, number of apoptotic cells was also reduced significantly in 17β-estradiol exposed rat pituitaries. The ratio of Bcl-2/Bax was significantly increased in 17β-estradiol exposed rat pituitaries as compared to untreated controls or 17α-estradiol exposed pituitaries. Hence, these studies suggest that imbalanced expression of Bcl-2 and Bax may be associated with estrogen-induced inhibition of apoptosis in rat pituitaries. Further in vitro studies indicate that carcinogenic estrogen is capable of modulating expression of Bcl-2 and Bax in rat pituitary tumor derived GH3 cells through complex molecular signaling pathways. Together, these in vivo and in vitro studies indicate that imbalanced expression of Bcl-2 and Bax is unique effect of carcinogenic estrogen and may be a critical event for tumorigenic switch.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]