ESTROGEN INDUCTION OF PITUITARY HYPERPLASIA

一个新的系统，其中研究肿瘤依赖性肿瘤生长， 以及正常生长的是雌激素诱导的垂体瘤。 17 β-雌二醇（E2）长期治疗（1-3个月）或 己烯雌酚导致诱发垂体瘤 Fischer 344（F344）大鼠（高泌乳素瘤），而Sprague-Dawley 衍生的（SD）菌株对这些肿瘤具有抗性。 我们已经进行 基因实验表明， 菌株之间的易感性不是由于单个基因性状，而是由于 可能是由于少量（2-4）基因。 短期（2-4天） 雌激素处理增加SD和F344的DNA合成 垂体 然而，在SD菌株中，DNA合成在5或10天后下降。 雌激素治疗6天，而DNA合成增加 在F344品系中，只要给予雌激素， 我们 工作假设是， 这些菌株是由于复制抑制机制， 在SD品系中抑制雌激素刺激的细胞增殖， 缺乏F344垂体。 本提案的总体目标是 是鉴定与雌激素诱导的 垂体生长和对敏感性或抵抗性 雌激素诱导的F344和SD大鼠肿瘤形成。 细胞复制和细胞周期调控的关键要素包括： 细胞周期蛋白，其似乎在G1和G2/M转换中起作用， 细胞周期 我们拟研究雌激素对垂体Gl 细胞周期蛋白基因表达，并确定细胞周期蛋白基因表达是否符合 我们之前提出的解释雌激素的遗传模型-- 诱导F344肿瘤。 这些研究可以扩展到已知的阻遏物 基因和其他必需的细胞周期基因。 我们还建议使用 消减杂交以鉴定菌株特异性基因产物， 因为细胞周期蛋白或其他参与生长调节的基因， 肿瘤依赖性系统。

A novel system in which to study both hormone-dependent tumor growth as well as normal growth is the estrogen induction of pituitary tumors. Prolonged treatment (1-3 months) with 17beta-estradiol (E2) or diethylstilbestrol results in the induction of pituitary tumors (hyperprolactinomas) in Fischer 344 (F344) rats whereas Sprague-Dawley derived (SD) strains are resistant to such tumors. We have conducted genetic experiments indicating that the difference in tumor susceptibility between strains was not due to a single gene trait but vas probably due to a small (2-4) number of genes. Short-term (2-4 days) treatment with estrogen increases DNA synthesis in both SD and F344 pituitaries. However, DNA synthesis declines in the SD strain after 5 or 6 additional days of estrogen treatment, whereas elevated DNA synthesis persists in the F344 strain as long as estrogen is administered. Our working hypothesis is that the difference in tumor susceptibility between the strains is due to a replication repression mechanism that functions in the SD strain to restrain estrogen-stimulated cell proliferation but is deficient in F344 pituitaries. The overall objective of this proposal is to identify specific gene product(s) that relate to estrogen-induced pituitary growth and to either susceptibility or resistance of estrogen-induced tumor formation in F344 and SD rats. Key elements in cell replication and cell cycle regulation include the cyclins, which appear to function in Gl and in the G2/M transition of the cell cycle. We propose to study estrogen regulation of pituitary Gl cyclin gene expression and determine whether cyclin gene expression fits the genetic models we have previously proposed to explain estrogen-- induced F344 tumors. These studies may be extended to known repressor genes and other essential cell cycle genes. We also propose to use subtractive hybridization to identify strain-specific gene products such as the cyclin or other genes involved in growth regulation in this hormone-dependent tumor system.