Progression and regression of mammary preneoplasia

乳腺肿瘤前期的进展和消退

• 批准号: 7279493
• 负责人: Priscilla A. Furth
• 金额: $ 3.1万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-23 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7279493
• 关键词: athymic mouse; biological signal transduction; brca gene; breast neoplasms; carcinogenesis; chemoprevention; cyclins; gene expression; green fluorescent proteins; growth factor; growth factor receptors; immunocytochemistry; neoplasm /cancer genetics; neoplasm /cancer remission /regression; neoplastic process; polymerase chain reaction; preneoplastic state; terminal nick end labeling; ultrasonography; western blottings

DESCRIPTION (provided by applicant): Long term aims: Understand how ERa driven breast cancers originate, develop more effective and less toxic approaches for chemoprevention, and determine if/how environmental and nutritional factors impact disease. This proposal will determine the role of three specific genetic factors in the development of breast preneoplasia and establish if they block regression of disease following hormone-based therapies. A novel conditional mouse model of mammary specific deregulated ERa expression that develops ductal hyperplasia and DCIS by 4 months of age will be used. The study will test if co-activators AIB1 and ?3AIB1, cell cycle regulator Cyclin D1, or loss of tumor suppressor gene Brca1 collaborate with ERa and/or compromise the response of preneoplasia and DCIS to anti-estrogen therapies. The hypothesis is that gain of AIB1, ?3AIB1, or Cyclin D1 function or loss of Brca1 function collaborate with ERa to promote mammary cancer initiation and progression and impair the response to anti-estrogen-based chemoprevention. Specific aims are: i. Determine how gain of AIB1 or ?3AIB1 or loss of AIB1 alters hormonal signaling patterns, development of ERa initiated preneoplasia and cancer or response to anti-estrogens, ii. Find out how gain or loss of Cyclin D1 alters development of ERa initiated preneoplasia and cancer and determine if changes in Cyclin D1 expression levels alter the response of preneoplasia to anti-estrogens, iii. Define how loss of full length Brca1 alters development of ERa initiated preneoplasia and cancer and test if loss of full-length Brca1 compromises the response to anti-estrogens. The combination of genetically engineered whole mouse models, mammary gland transplants and mammary gland organ cultures will be used to identify specific pathophysiological mechanisms including changes in hormone responsiveness, variations in gene expression and activity, and altered epithelial-stromal interactions. Pathophysiological changes will be followed in vivo in real-time using ultrasonography and green flourescent protein-based technology.

描述（由申请人提供）：长期目的：了解ERA驱动的乳腺癌如何起源，开发更有效，更少的毒性方法，以进行化学预防，并确定环境和营养因素是否影响疾病。该建议将确定三个特定遗传因素在乳腺癌发展中的作用，并确定它们是否阻止了基于激素的疗法后疾病的回归。将使用一种新型的乳腺特异性消除ERA表达的小鼠模型，该模型将在4个月大时在4个月大时才形成导管增生和DCI。该研究将测试共激活剂AIB1和？3AIB1，细胞周期调节剂Cyclin D1或肿瘤抑制基因BRCA1与ERA合作和/或损害了前肿瘤和DCIS对抗雌激素疗法的反应。假设是AIB1，？3AIB1或Cyclin D1功能或BRCA1功能的丧失与ERA合作，以促进乳腺癌的启动和进展，并损害对基于抗雌激素的化学预防的反应。具体目的是：i。确定AIB1或？3AIB1或AIB1的损失如何改变荷尔蒙信号传导模式，ERA的发育引发了肿瘤和癌症或对抗雌激素的反应，ii。找出细胞周期蛋白D1的增加或丧失如何改变ERA的发育引发的肿瘤和癌症，并确定细胞周期蛋白D1表达水平的变化是否改变了促脑质质对抗雌激素的反应，III。确定全长BRCA1的损失如何改变ERA的发展产生了蓬罗氏症和癌症，并测试了全长BRCA1是否损害了对抗雌激素的反应。基因设计的整个小鼠模型，乳腺移植和乳腺器官培养物的结合将用于确定特定的病理生理机制，包括激素反应性的变化，基因表达和活性的变化以及改变上皮 - 层状相互作用。使用超声检查和绿色含量蛋白质的技术，将在体内实时遵循病理生理的变化。