Progression and regression of mammary preneoplasia

_ROVIDED。 长期目标：了解ER a驱动的乳腺癌如何起源，开发更有效和毒性更低的药物 化学预防方法，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腺发育中的作用 肿瘤前病变，并确定它们是否阻止基于肿瘤的治疗后疾病的消退。一种新型 发生导管增生的乳腺特异性ER α表达失调的条件小鼠模型 将使用4个月龄的DCIS。本研究将检测共激活剂AIB 1和A3 AIB 1、细胞周期 调节细胞周期蛋白D1，或肿瘤抑制基因Brcal的缺失与ER α合作和/或损害细胞周期蛋白D1的表达。 癌前病变和DCIS对抗雌激素治疗的反应。假设AIB 1，A3 AIB 1， 或Cyclin D1功能或Brcal功能缺失与ER α协同促进乳腺癌的发生 并损害对抗雌激素化学预防的反应。具体目标是：一。 确定AIB 1或A3 AIB 1的获得或AIB 1的丧失如何改变激素信号模式， ER α引发的瘤前病变和癌症的发展或对抗雌激素的应答，ii.了解如何获得或 细胞周期蛋白D1的丢失改变了ER α启动的癌前病变和癌症的发展，并确定细胞周期蛋白D1的变化是否会影响ER α的表达。 细胞周期蛋白D1的表达水平改变的反应癌前抗雌激素，iii。如何定义完全丧失- 长度Brcal改变ER α引发的瘤前病变和癌症的发展，并测试全长Brcal是否丢失 会影响抗雌激素的反应基因工程整只老鼠 模型、乳腺移植和乳腺器官培养将用于鉴定特定的 病理生理机制，包括激素反应性的变化，基因变异， 表达和活性以及改变的上皮-基质相互作用。病理生理变化将是 随后使用超声和基于绿色荧光蛋白的技术在体内实时检测。

_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.