Progression and regression of mammary preneoplasia

乳腺肿瘤前期的进展和消退

• 批准号: 7740957
• 负责人: Priscilla A. Furth
• 金额: $ 8.9万
• 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 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740957
• 关键词: Adenocarcinoma; Affect; Age-Months; BRCA1 gene; Breast; Cell Cycle; Chemoprevention; Cyclin D1; Data; Development; Disease; Disease regression; Ductal; Engineering; Epithelial; Epithelial Cells; Epithelial-Stromal Communication; Estrogen Antagonists; Estrogen Therapy; Estrogens; Functional disorder; Gene Expression; Genetic; Green Fluorescent Proteins; Growth; Growth and Development function; Hormonal; Hormones; Human; Image; Interruption; Intraductal Hyperplasia; Length; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Measures; Modeling; Molecular; Mutation; NCOA3 gene; Neonatal; Noninfiltrating Intraductal Carcinoma; Nuclear; Nutritional; Organ Culture Techniques; Pattern; Principal Investigator; Protein Isoforms; Proteins; Research Design; Role; Signal Pathway; Signal Transduction; Stromal Cells; Structure; Techniques; Technology; Testing; Time; Tissues; Transgenic Mice; Transplantation; Tumor Suppressor Genes; Ultrasonography; Variant; animal tissue; base; cancer initiation; human disease; in vivo; malignant breast neoplasm; mouse model; novel; pre-clinical; programs; research study; response; time use

_ROVIDED. 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 A3AIB1, cell cycle regulator Cyclin D1, or loss of tumor suppressor gene Brcal collaborate with ERa and/or compromise the response of preneoplasia and DCIS to anti-estrogen therapies. The hypothesis is that gain of AIB1, A3AIB1, or Cyclin D1 function or loss of Brcal function collaborate with ERa to promote mammary cancer initiation and progressionand impair the response to anti-estrogen-based chemoprevention. Specific aims are: i. Determine how gain of AIB1 or A3AIB1 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 Brcal alters development of ERa initiated preneoplasia and cancer and test if loss of full-length Brcal 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.

_ROVIDED。 长期目的：了解时代驱动的乳腺癌如何产生，发展更有效，毒性更少 化学预防的方法，并确定环境和营养因素如何影响疾病。 该建议将确定三个特定遗传因素在乳房发展中的作用 肿瘤质量并确定基于激素的疗法后，它们是否阻止了疾病的回归。小说 有条件的乳腺特异性失调ERA表达的小鼠模型，该模型发展为导管增生 将使用4个月大的DCI。该研究将测试共激活剂AIB1和A3AIB1，细胞周期 调节剂细胞周期蛋白D1，或失去抑制肿瘤基因BRCAL与ERA合作和/或妥协 肿瘤和DCI对抗雌激素疗法的反应。假设是AIB1，A3AIB1的获得 或Cyclin D1功能或BRCAL功能的丧失与ERA合作以促进乳腺癌的启动 进展和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A3AIB1或AIB1的损失的增益如何改变激素信号传导模式， ERA的发展引发了肿瘤和癌症或对抗雌激素的反应，ii。找出收益或 细胞周期蛋白D1的丧失会改变ERA的发展引发的肿瘤和癌症，并确定是否发生变化 细胞周期蛋白D1表达水平改变了肿瘤对抗雌激素的反应，iii。定义失去全部损失 长度BRCAL改变ERA的开发开始引发肿瘤和癌症，并测试全长BRCAL的丧失 损害对抗雌激素的反应。基因设计的整个鼠标的结合 模型，乳腺移植和乳腺器官培养物将用于识别特定 病理生理机制，包括激素反应性的变化，基因变化 表达和活性，改变了上皮 - 层相互作用。病理生理的改变将是 随后是使用超声检查和绿色含量蛋白质技术实时体内的。