Conditional Knockdown Mouse Models for Mammary Tumorigenesis

描述（由申请人提供）：乳腺癌代表了每年报告的新癌症诊断的重要部分。为了了解不同类型的乳腺癌是如何产生的，我们需要确定乳腺肿瘤发生的其他病因。在人类乳腺肿瘤样本的初步研究中，大约33%的病例中BCCIP水平异常，其中三阴性乳腺癌（TNBC）中45%，非TNBC中25%。我们假设乳腺组织中的BCCIP缺陷有助于肿瘤的发生，特别是散发性TNBC。为了验证这一假设，我建议在小鼠乳腺的特定细胞类型中使用Cre-LoxP介导的BCCIP条件敲低。本研究的初步数据表明，肌上皮细胞中BCCIP下调可导致离散病变的发生。在对照动物中没有观察到这种生长。对于我接下来的培训阶段，我提出了三个目标，以进一步验证这一假设，并解决BCCIP缺乏在乳腺肿瘤发生中的病因学作用。目的1将检测并分子表征BCCIP缺陷小鼠形成的自发性乳腺癌，以验证BCCIP缺陷可能导致三阴性癌症的假设。Aim 2将在BCCIP缺陷小鼠模型中使用辐射诱导乳腺癌，验证BCCIP在DNA损伤诱导乳腺癌中发挥作用的假设，并确定BCCIP在乳腺对DNA损伤反应中的作用。目的3将使用体外和体内方法来了解BCCIP缺陷导致乳腺上皮细胞基因组不稳定的机制。

DESCRIPTION (provided by applicant): Breast cancer represents a significant portion of the new cancer diagnosis reported yearly. To understand how different breast cancers types arise, we need to identify additional etiological factors for mammary tumorigenesis. In a preliminary study of human breast tumor samples, BCCIP levels were abnormal in approximately 33% of the cases, including 45% among Triple Negative Breast Cancer (TNBC) and 25% among in non- TNBC. We hypothesize that BCCIP defects in mammary tissue contribute to tumorigenesis, particularly of sporadic TNBC. To test the hypothesis I proposed to use a Cre-LoxP mediated BCCIP conditional knockdown in specific cell types of the mouse mammary gland. Preliminary data of this study suggest BCCIP downregulation in myoepithelial cells causes development of discrete lesions. Such growth has not been observed in the control animals. For the following phase of my training, I propose three aims to further test the hypothesis and address the etiological roles of BCCIP deficiency in mammary tumorigenesis. Aim 1 will detect and molecularly characterize the spontaneous breast cancer formed in BCCIP deficient mice to test the hypothesis that BCCIP deficiency preferably causes triple negative cancer. Aim 2 will use radiation induced breast cancer in the BCCIP deficient mouse model to test the hypothesis that BCCIP plays a role in DNA damage induced breast cancer, and to identify the role of BCCIP in mammary response to DNA damage. Aim 3 will use in vitro and in vivo approaches to understand the mechanisms by which BCCIP deficiency contribute to genomic instability in the mammary epithelial cells.