The DNA double-strand repair genes BARD1 and RAD51 as molecular targets for brain metastases from breast cancer

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-28

* FARE Award Winner

Authors

• S Woditschka
• D Palmieri
• GW Sledge
• S Badve
• PS Steeg

Abstract

High expression of the DNA double-strand break (DSB) repair genes BARD1 and RAD51 in HER+ breast tumors was predictive of rapid brain metastasis development as part of a 13-gene signature. BARD1 and RAD51 were overexpressed in resected brain metastases compared to primary breast tumors from the same women (1.5-fold, p=0.0008; 1.5-fold, p=0.001, respectively) and systemic (lung/bone) metastases (1.5-fold, p=0.01; 1.4-fold, p=0.008, respectively). We overexpressed BARD1 and RAD51 at physiologically relevant levels in a brain-metastatic variant of triple-negative MDA-MB-231 breast carcinoma cells. In vitro, this resulted in a 30% increase in clonogenic colony formation (BARD1 p=0.001, RAD51 p=0.004), without affecting cell proliferation rates. Overexpression also conferred chemoresistance to DNA DSB inducing chemotherapeutics, such as carboplatin (BARD1 p=0.005, RAD51 p=0.03) and doxorubicin (BARD1 p=0.03, RAD51 p=0.02). In vivo, overexpression of BARD1 and RAD51 resulted in a 3-4-fold increase of large brain metastases, (p=0.002, p=0.01, respectively) and micro-metastases (p=0.001, p=0.01, respectively) compared to vector controls in a mouse xenograft model. Together these data suggest a driving role for BARD1 and RAD51 in the development of brain metastases from breast cancer. Since these genes are overexpressed in a brain metastasis-specific manner, they represent potentially novel targets for brain metastasis treatment and prevention.

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