Progression and regression of mammary preneoplasia

_ROVIDED。 长期目标：了解时代驱动的乳腺癌是如何起源的，发展得更有效，毒性更低 化学预防的方法，并确定环境和营养因素是否/如何影响疾病。 这项建议将确定三个特定的遗传因素在乳房发育中的作用 并确定它们是否会阻止激素治疗后疾病的消退。一本小说 乳腺特异失控Era表达发展为导管增生症的条件性小鼠模型 和4个月大的DCIS将被使用。这项研究将测试共同激活剂AIB1和A3AIB1是否会影响细胞周期 调控因子Cyclin D1，或肿瘤抑制基因Brcal的丢失与ERA协同和/或损害 创业症和DCIS对抗雌激素治疗的反应。假设AIB1、A3AIB1 或Cyclin D1功能或Brcal功能丧失与ERA协同促进乳腺癌的发生 和进展，并损害对以抗雌激素为基础的化学预防的反应。具体目标是：i. 确定AIB1或A3AIB1的增加或AIB1的丢失如何改变激素信号模式， Era的发展引发了创业和癌症或对抗雌激素的反应，2。了解如何获得或 Cyclin D1的丢失改变了Era启动的创业和癌症的发生，并决定了 Cyclin D1的表达水平改变了创业症对抗雌激素的反应，III。定义如何完全失去- 长度支气管炎改变时代开始的创业和癌症的发展以及全长支气管炎是否丢失的检测 会影响对抗雌激素药物的反应。转基因整只小鼠的组合 将使用模型、乳腺移植和乳腺器官培养来识别特定的 包括激素反应变化、基因变异在内的病理生理机制 表达和活性，以及改变的上皮-间质相互作用。病理生理变化将是 随后在活体内实时使用超声和绿色荧光蛋白技术。

_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.