Progression and regression of mammary preneoplasia

描述（由申请人提供）：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小的化学预防方法，并确定环境和营养因素是否/如何影响疾病。这项提案将确定三个特定的遗传因素在乳腺癌前病变的发展中的作用，并确定它们是否会阻止基于乳腺癌的治疗后疾病的消退。将使用一种乳腺特异性ER α表达失调的新型条件性小鼠模型，该模型在4月龄时发生导管增生和DCIS。该研究将测试是否共激活剂AIB 1和？3AIB 1、细胞周期调节因子Cyclin D1或肿瘤抑制基因Brca 1的缺失与ER a协同作用和/或损害癌前病变和DCIS对抗雌激素治疗的反应。假设AIB 1，？3AIB 1或Cyclin D1功能或Brca 1功能的丧失与ER a协同促进乳腺癌的发生和进展，并损害对基于抗雌激素的化学预防的反应。具体目标是：一。确定AIB 1或？3AIB 1或AIB 1的丧失改变激素信号传导模式、ER α引发的瘤前病变和癌症的发展或对抗雌激素的反应，ii.找出细胞周期蛋白D1的获得或损失如何改变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表达水平的变化是否会改变癌前病变对抗雌激素的反应，iii.定义全长Brca 1的丢失如何改变ER α启动的癌前病变和癌症的发展，并测试全长Brca 1的丢失是否会影响对抗雌激素的反应。基因工程整只小鼠模型、乳腺移植和乳腺器官培养的组合将用于鉴定特定的病理生理机制，包括激素反应性的变化、基因表达和活性的变化以及上皮-基质相互作用的改变。将使用超声和基于绿色荧光蛋白的技术在体内实时跟踪病理生理变化。

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.