GENETIC AND BIOCHEMICAL DISSECTION OF PROLACTIN ACTIONS

催乳素作用的遗传学和生物化学剖析

• 批准号: 2905953
• 负责人: Nelson D Horseman
• 金额: $ 28.65万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2905953
• 关键词: age difference; breast neoplasms; carcinogenesis; cell differentiation; cell growth regulation; cell transplantation; chemical carcinogen; estradiol; female; gene expression; gene targeting; genetic markers; genetically modified animals; homologous transplantation; hormone receptor; hormone regulation /control mechanism; hormone related neoplasm /cancer; laboratory mouse; mammary epithelium; mammary gland; ovariectomy; phenotype; progesterone; prolactin; tumor promoters

One of this laboratory's long term goals is to contribute to a better understanding of prolactin's actions and signaling mechanisms. To support this goal we have developed a novel mouse model in which the prolactin (PRL) gene has been disrupted and propose here to study the regulation of mammary gland function using these mice. PRL actions in mammary gland growth and breast cancer remain controversial. The discovery that PRL is secreted locally in the mammary gland raises new controversies about PRL as a tumor cell growth factor. PRL knockout (PRLKO) mice provide a novel model system with which to clarify the role of PRL in breast cancer. The overall goal is to test the hypothesis that PRL is a differentiative signal that drives mammary gland maturation in balance with the proliferative effects of estradiol. This hypothesis makes specific predictions that will be challenged through experiments in four specific aims. Aim 1 will test the prediction that PRL treatment of PRLKO mice promotes differentiative phenotypic changes in the mammary gland. Differentiation-associated markers are predicted to be deficient in the mammary gland of virgin PRLKO mice. To test this measurements will be made of morphological, proliferative, apoptotic and immunocytochemical changes in the mammy gland epithelium and extracellular matrix of mice treated, or not, with PRL. The expression levels and activation of Jak2, Stat5a/b, Stat1 will be compared in PRLKO and normal mice. Aim 2 will use PRLKO mice to test the interactions between ovarian steroids and PRL by assaying changes in proliferation and differentiation markers in the mammary gland. Ovariectomized mice, treated or not with estradiol, progesterone and PRL will be used for these studies. Aim 3 will test the hypothesis that local PRL contributes to phenotypic differentiation of the mammary gland. Mammary gland tissues from normal mice will be transplanted into PRLKO mice to determine if local PRL alters epithelial function. Reciprocal transplantations will be done to determine if PRLKO mammary tissue can be stimulated to normal development through puberty, pregnancy and lactation. Aim 4 will test the effects of PRL on initiation and progression of mammary gland tumors in PRLKO mice. PRL may have different effects on tumor initiation and tumor growth because of its dual actions as a differentiation and trophic hormone. PRL will be given before and/or after carcinogen (DMBA) exposure to determine its effects on tumorigenesis. These experiments are essential for understanding PRL actions in mammary gland and breast cancer.

该实验室的长期目标之一是为更好的 了解催乳素的作用和信号机制。 到 为了支持这一目标，我们开发了一种新颖的小鼠模型，其中 催乳素（PRL）基因已被破坏，建议在此研究 使用这些小鼠调节乳腺功能。 PRL 行动 乳腺生长和乳腺癌仍然存在争议。 这 PRL 在乳腺局部分泌的发现提出了新的观点 关于 PRL 作为肿瘤细胞生长因子的争议。 PRL敲除 (PRLKO) 小鼠提供了一种新的模型系统来阐明其作用 PRL 在乳腺癌中的作用。 总体目标是检验假设 PRL 是驱动乳腺的分化信号 成熟与雌二醇的增殖作用平衡。 这 假设做出了具体的预测，这些预测将受到挑战 实验有四个具体目标。 目标 1 将测试以下预测： PRL 治疗 PRLKO ​​小鼠促进分化表型变化 在乳腺中。预测分化相关标记 处女 PRLKO ​​小鼠的乳腺有缺陷。 为了测试这个 测量将进行形态学、增殖、凋亡和 乳腺上皮细胞的免疫细胞化学变化 用或未用 PRL 处理的小鼠的细胞外基质。 表达式 Jak2、Stat5a/b、Stat1 的水平和激活将在 PRLKO ​​中进行比较 和正常小鼠。 目标 2 将使用 PRLKO ​​小鼠来测试相互作用 通过检测增殖的变化来比较卵巢类固醇和 PRL 之间的关系 和乳腺中的分化标记。 切除卵巢的小鼠， 无论是否经过雌二醇、黄体酮和 PRL 治疗，均将用于 这些研究。 目标 3 将检验本地 PRL 的假设 有助于乳腺的表型分化。乳腺 正常小鼠的腺体组织将被移植到 PRLKO ​​小鼠体内 确定局部 PRL 是否会改变上皮功能。互惠的 将进行移植以确定 PRLKO ​​乳腺组织是否可以 通过青春期、怀孕和 哺乳期。 目标 4 将测试 PRL 对启动和启动的影响 PRLKO ​​小鼠乳腺肿瘤的进展。 PRL 可能有 由于其对肿瘤发生和生长的影响不同 作为分化激素和营养激素的双重作用。 PRL 将是 在接触致癌物（DMBA）之前和/或之后给予以确定其 对肿瘤发生的影响。 这些实验对于 了解 PRL 在乳腺和乳腺癌中的作用。