BRCA1 Pathway Function in Basal-Like Breast Cancer Cells

Abstract

Sporadic basal-like cancers (BLCs) are a common subtype of breast cancer that share multiple biological properties with BRCA1-mutated breast tumors. Despite being BRCA1^+/+, sporadic BLCs are widely viewed as phenocopies of BRCA1-mutated breast cancers, because they are hypothesized to manifest a BRCA1 functional defect or breakdown of a pathway(s) in which BRCA1 plays a major role. The role of BRCA1 in the repair of double-strand DNA breaks by homologous recombination (HR) is its best understood function and the function most often implicated in BRCA1 breast cancer suppression. Therefore, it is suspected that sporadic BLCs exhibit a defect in HR. To test this hypothesis, multiple DNA damage repair assays focused on several types of repair were performed on a group of cell lines classified as sporadic BLCs and on controls. The sporadic BLC cell lines failed to exhibit an overt HR defect. Rather, they exhibited defects in the repair of stalled replication forks, another BRCA1 function. These results provide insight into why clinical trials of poly(ADP-ribose) polymerase (PARP) inhibitors, which require an HR defect for efficacy, have been unsuccessful in sporadic BLCs, unlike cisplatin, which elicits DNA damage that requires stalled fork repair and has shown efficacy in sporadic BLCs.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01646-13.

ACKNOWLEDGMENTS

We thank Kristine McKinney for valuable experimental advice, Christian Colin for advice on Southern blotting, and Kristine McKinney and other members of the D. M. Livingston lab for helpful discussions.

S.J.H. was initially funded by DOD BCRP fellowship W81XWH-08-1-0748 and subsequently by NCI fellowship 1F30CA167895-01. This work was supported by grants from the Susan G. Komen Foundation for the Cure (SAC110022), the Breast Cancer Research Foundation, an NCI SPORE grant (P50CA089393) in breast cancer research to the Dana-Farber/Harvard Cancer Center, and RO1 (R01CA136512) and P01 (P01CA080111) grants from NCI to D.M.L.

S.J.H., D.M.L., and D.P.S. conceived of the project, and D.M.L. and D.P.S. mentored S.J.H. in its execution. A.P.C. performed the Southern blotting assays whose results are shown in Fig. 5A. S.J.H. performed all other experiments and wrote the manuscript. S.J.H., D.M.L., A.P.C., and D.P.S. collectively edited the manuscript.