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Modulation of Mammary Tumorigenesis by BCCIP Dysfunction

Roberto M. Droz- Rosario
B.S., University of Puerto Rico, Rio Piedras- 2006

Thesis Advisor: Zhiyuan Shen, M.D., Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

Rutgers Cancer Institute of NJ
Auditorium A,
195 Little Albany St, New Brunswick

Thursday, February 19, 2015
10:00 a.m..


DNA repair is considered essential in suppression of mammary tumorigenesis. Particularly, homologous recombination (HR) and controlled proliferation are critical for maintenance of genomic integrity. This is necessary to ensure mammary gland homeostasis through the repeated cycles of expansion, differentiation and regression in response to hormonal cues. Thus defective HR and dysregulated cell proliferation could become sources of instability that initiate neoplastic transformation. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein that has been implicated in maintenance of genomic stability because of its roles in HR and regulation of p53-p21 mediated control of cell proliferation and cell cycle progression. In this study, two conditional mouse models were used to evaluate the role of BCCIP deficiency in modulating mammary tumorigenesis. In one the BCCIP gene was conditionally knocked out while the other achieved BCCIP silencing through conditional expression of an shRNA oligo against BCCIP. Partial but not complete loss of BCCIP in the mammary epithelium promoted the development of benign latent mammary nodules in a significant number of females with reduced BCCIP levels. While majority of these lesions remained latent and did not progress to malignant tumors, some of them developed into malignant tumors upon additional genetic events. Interestingly, de novo malignant mammary tumors were detected at a lower frequency in animals with reduced BCCIP levels when compared to those with normal BCCIP levels. This suggests that BCCIP dysfunction is necessary for the initial events that initiate tumor formation, but is required to sustain cell proliferation and tumor growth during progression to disease. Loss of p53 function or exposure to low doses of ionizing radiation (IR) did not seem to have an epistasis in BCCIP related mammary tumors. However, BCCIP deficient tumors have histopathological similarities to other mouse models for HR deficient breast cancer. Moreover, loss of p16 and 53BP1 in these tumors suggest that secondary genetic alterations were necessary to compensate for BCCIP deficiency and sustain tumor progression. In summary, this study suggest BCCIP plays a significant role in modulating mammary tumorigenesis and it further supports BCCIP as a tumor suppressor with genome caretaker functions, but that is required for tumor progression.

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