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: 2638399
• 负责人: Nelson D Horseman
• 金额: $ 28.81万
• 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/2638399
• 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地 了解催乳素的作用和信号机制。至 为了支持这一目标，我们开发了一种新的鼠标模型，在该模型中 催乳素(PRL)基因已被打乱，建议在此研究 利用这些小鼠调节乳腺功能。中的PRL操作 乳腺生长和乳腺癌仍然存在争议。这个 催乳素在乳腺局部分泌的发现带来了新的 关于PRL作为一种肿瘤细胞生长因子的争论。PRL淘汰赛 (PRLKO)小鼠提供了一种新的模型系统，用来阐明其作用 PRL在乳腺癌中的表达。总体目标是检验这一假设 催乳素是驱动乳腺的分化信号 成熟与雌二醇的增殖作用相平衡。这 假说做出了特定的预测，这些预测将通过 在四个具体目标上进行实验。目标1将验证这样的预测 PRL治疗PRLKO小鼠促进分化表型改变 在乳腺里。预测与分化相关的标记 在处女PRLKO小鼠的乳腺中存在缺陷。为了测试这一点 将进行形态、增殖、凋亡和 乳头腺上皮和乳房的免疫细胞化学变化 无论是否用催乳素处理的小鼠细胞外基质。表达方式 将比较PRLKO中JAK2、Stat5a/b、STAT1的水平和激活 和正常的小鼠。AIM 2将使用PRLKO小鼠来测试相互作用 卵巢类固醇激素与催乳素之间的关系 和乳腺中的分化标志物。去卵巢的小鼠， 无论是否接受雌二醇、黄体酮和催乳素的治疗， 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。乳房 将正常小鼠的腺体组织移植到PRLKO小鼠体内 确定局部PRL是否改变上皮功能。互惠 将进行移植以确定PRLKO乳腺组织是否可以 通过青春期、妊娠期和青春期刺激到正常发育 哺乳。目标4将测试催乳素对启动和 PRLKO小鼠乳腺肿瘤的研究进展。PRL可能有 对肿瘤的启动和生长有不同的影响 作为一种分化和营养激素的双重作用。PRL将成为 在接触致癌物(DMBA)之前和/或之后给药，以确定其 对肿瘤发生的影响。这些实验对于 了解催乳素在乳腺和乳腺癌中的作用。