BIOLOGY AND ENDOCRINOLOGY OF THE RESISTANT MAMMARY GLAND

大量实验表明，怀孕会产生一种保护作用 对抗啮齿动物和人类乳腺肿瘤的发展。 这种保护作用可以在大鼠身上通过给药来模拟 化疗前的雌激素和黄体酮。几个问题 关于荷尔蒙诱导对乳腺的保护作用 肿瘤发生机制仍未得到解答。这些问题涉及到剂量和 诱导保护状态所需激素的持续时间，稳定性 处于保护状态。该项目涉及三个具体目标，即 都与理解细胞和分子基础有关 起到了保护作用。为解决这些目标而选择的模型是N-甲基-N- 亚硝脲(MNU)诱发近交系Wistar-Furth乳腺肿瘤 用雌激素和黄体酮处理的大鼠。具体目标1确定 产生保护作用所需的最小激素剂量和时间。 TGFbeta II的表达将在抗性蚂蚁和 敏感乳腺为耐药细胞提供终点 表型。特定目标2检查抵抗状态的持久性 FY分别于实验结束后28、78和128天给予大鼠MNU 激素治疗。《特定目标3》研究了抗药性是否存在 在乳腺实质或间质间隔内使用 乳房脂肪垫移植系统。从处女腺和腺体 经过激素处理的动物将被移植到大鼠体内，并检查 他们各自对MNU的易感性。具体目标4将确立 敏感和耐药乳腺上皮细胞株的建立 和MNU诱发的乳腺肿瘤。这些细胞系将被用作 用于转基因实验的受体细胞，以检测 在其他项目中分离的特定基因的过度表达。结果是 这些实验将建立一个最低限度的荷尔蒙治疗方案 实验性乳腺癌的预防和坚实的理论基础 发展激素干预是治疗人类癌症的可行方法 预防。

Numerous experiments have shown that pregnancy induces a protective effect against tumor development in the mammary glands of both rodents and humans. This protective effect can be mimicked in rats by administration of estrogen and progesterone prior to chemical treatment. Several questions regarding athe hormonal induction of the protective effect on mammary tumorigenesis remain unanswered. These questions involve the dose and duration of hormones required to induce a protective state, the stability of the protective state. This project addresses three specific aims which are relevant to understanding the cellular and molecular basis of the protective effect. The model chosen to address these aims is N-methyl-N- nitrosourea (MNU) induced mammary tumorigenesis in inbred Wistar-Furth rats pretreated with estrogen and progesterone. Specific aim 1 determines the minimum hormone doses and time required to induce a protective effect. The expression of TGFbeta II will be assessed in the resist ant and susceptible mammary gland to provide an endpoint for the resistant cell phenotype. Specific Aim 2 examines the persistence of the resistant state fy administering MNU to rats at 28, 78 and 128 days after the end of hormone treatment. Specific Aim 3 examines whether resistance resides within the mammary gland parenchyma or stromal compartment using the mammary fat pad transplantation system. Glands from both virgin and hormone-treated animals will be transplanted into rats and examined for their respective susceptibility to MNU. Specific Aim 4 will establish mammary epithelial cell lines from susceptible and resistant mammary glands and from MNU-induced mammary tumors. These cell lines will be used as recipient cells for transfection experiments examining the consequences of overexpression of specific genes isolated in other projects. The results of these experiments will establish a minimal hormonal regiment for prevention of experimental breast cancer and a firm rationale for developing hormonal intervention as a feasible approach for human cancer prevention.