Conditional Knockdown Mouse Models for Mammary Tumorigenesis

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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. PUBLIC HEALTH RELEVANCE: The molecular etiology of breast cancer has been not been fully elucidated. Based on a preliminary study with more than 400 cases, ~1/3 of the breast cancers lost BCCIP expression, including 49% of the triple negative breast cancer. This study will generate a transgenic mouse model to address the mechanisms by which BCCIP deficiency contributes development of breast cancer. Completion of the study will help us to understand events that lead to cancer and potentially contribute to develop better ways to appropriately diagnose, and treat patients according to the molecular profile of their disease.