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53BP1 Abnormalities in Basal like
Breast Cancer

Amal Salem Aly
M.B., Ch.B., M.S., Al Azhar University
Medical School for Women
Cairo, Egypt - 1997

Thesis Advisor: Shridar Ganesan, M.D., Ph.D.
Graduate Program in Molecular & Cellular Pharmacology

The Child Health Institute of New Jersey
Room 3101
New Brunswick

Tuesday, March 29, 2011
2:00 p.m.


The BRCA1 tumor suppressor plays a critical role in homology mediated repair of DNA double strand breaks. The DNA repair defects present in BRCA1-mutant cancers renders them exquisitely sensitive to inter-strand crosslinking agents and PARP inhibitors. The majority of breast cancers that arise in BRCA1-mutation carrier’s cluster with a specific molecular subclass: basal-like breast cancer (BLC). This observation suggests that sporadic BLC may also have defects in DNA repair similar to that seen in BRCA1-associated breast cancers, and has led to clinical trials evaluating ICL and PARP inhibitors for sporadic BLC.
We now report that a subset of both sporadic and BRCA1-associated BLC have abnormally low expression of the DNA repair and checkpoint protein p53 binding protein 1 (53BP1). Abnormal expression of 53BP1 is present in some human basal-like breast cancer cell lines, and an acquired somatic mutation of 53BP1 was found in a mouse Brca1-mutant breast cancer cell line.
Functional studies demonstrated that loss of 53BP1 can alleviate the growth arrest normally associated with acute deletion of Brca1 in mouse ES cells. Loss of 53BP1 in Brca1-mutant cells also leads to partial restoration of homology-mediated DNA repair, and resistance to interstrand crosslinking agents. This effect is specific for Brca1, as loss of 53BP1 had no such effect in Brca2 mutant cells. Thus loss of 53BP1 can act as a compensating mutation for the repair defect in Brca1-mutant cells and partially restore homology- PARP inhibitors. 53BP1 expression may be a biomarker to predict sensitivity of both BRCA1-mutant and “BRCA1-like” sporadic basal-like breast cancers to these agents. These data demonstrate that acquired loss of 53BP1 may contribute to resistance of BRCA1-mutant cancers to interstrand crosslinking agents and PARPi.

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