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: 6381314
• 负责人: Nelson D Horseman
• 金额: $ 30.46万
• 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 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381314
• 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促进更好的 了解催乳素的作用和信号机制。 到 为了支持这一目标，我们开发了一种新的小鼠模型， 催乳素（PRL）基因已被破坏，并建议在这里研究 调节乳腺功能。 PRL行动 乳腺生长和乳腺癌仍然存在争议。 的 发现催乳素在乳腺局部分泌， 关于PRL作为肿瘤细胞生长因子的争议。 PRL基因敲除 （PRLKO）小鼠提供了一种新的模型系统， PRL在乳腺癌中的作用 总体目标是检验假设 PRL是一种分化信号， 成熟与雌二醇的增殖作用平衡。 这 假设做出了具体的预测，将受到挑战， 四个具体目标的实验。 目标1将检验预测， PRLKO小鼠的PRL治疗促进分化表型变化 在乳腺中。预测分化相关标志物 在PRLKO小鼠的乳腺中缺乏。 为了验证这一 将对细胞的形态学、增殖、凋亡和 乳腺上皮细胞的免疫细胞化学变化， 用PRL处理或未处理的小鼠的细胞外基质。 表达 将在PRLKO中比较Jak 2、Stat 5a/B、Stat 1的水平和活化 正常的老鼠。 目标2将使用PRLKO小鼠来测试相互作用 卵巢类固醇和催乳素之间的关系， 和乳腺中的分化标志物。 卵巢切除小鼠， 用雌二醇、孕酮和PRL治疗或未治疗的患者将用于 这些研究。 目标3将检验局部PRL 有助于乳腺的表型分化。乳腺 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、怀孕和 哺乳期 目的4将测试PRL对启动和 PRLKO小鼠中乳腺肿瘤的进展。 PRL可能有 对肿瘤发生和肿瘤生长的不同影响， 作为分化和营养激素的双重作用。 PRL将是 在致癌物（DMBA）暴露之前和/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。