Progression and regression of mammary preneoplasia

描述（由申请人提供）：长期目标：了解ERa驱动的乳腺癌是如何产生的，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。该建议将确定三种特定遗传因素在乳腺瘤前病变发展中的作用，并确定它们是否阻断激素治疗后疾病的消退。我们将使用一种新的乳腺特异性ERa表达失调的条件小鼠模型，该模型在4月龄时发生导管增生和DCIS。该研究将测试AIB1和？3AIB1、细胞周期调节因子Cyclin D1或肿瘤抑制基因Brca1的缺失与ERa共同作用和/或损害瘤前病变和DCIS对抗雌激素治疗的反应。假设是AIB1的增益？3AIB1或Cyclin D1功能或Brca1功能缺失与ERa共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：i.确定AIB1的增益或？AIB1或AIB1的缺失会改变激素信号模式、ERa引发的瘤前病变和癌症的发展或对抗雌激素的反应。了解Cyclin D1的获得或缺失如何改变ERa引发的瘤前病变和癌症的发展，并确定Cyclin D1表达水平的变化是否改变瘤前病变对抗雌激素的反应。定义全长Brca1的缺失如何改变ERa引发的瘤前病变和癌症的发展，并检测全长Brca1的缺失是否会影响抗雌激素的反应。基因工程全鼠模型、乳腺移植和乳腺器官培养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上皮-基质相互作用的改变。利用超声和基于绿色荧光蛋白的技术实时跟踪体内病理生理变化。

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.