Abstract 3720: Rad51 is involved in PARP inhibitor resistance in triple-negative breast cancer stem cells (TNBCSCs)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-04, Vol.73 (8_Supplement), p.3720-3720
• Main Authors: Liu, Yajing, Martin, Rachel, Bai, Shoumin, Wicha, Max, Liu, Suling
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2013-3720

Although the mortality rate in breast cancer (BC) has been reduced by the advancing technology, the outcome of patients with “triple-negative” (TN) BC (accounts for 10-17% of invasive BC) has achieved little progression. Recently, inhibitors of poly (adenosine-disposphate-ribose) polymerase (PARP) have been developed to target cells with defective DNA repair molecules such as BRCA1-deficient cells. Despite the tumor regression induced by these agents in a subset of BCs, their ability to effect patient outcome remains inconclusive. According to the CSC hypothesis, a hierarchical tumor organization exists whereby dysregulated self-renewing CSCs drive tumorigenesis. Our preliminary results showed that PARP inhibitor significantly decreased cell number in BRCA1-deficient SUM149 cells in a dose-dependent manner, whereas BRCA1 wild type SUM159 cells were relatively resistant. However, there was little change in absolute CSC number in SUM149 cells after PARP inhibitor treatment, suggesting PARP inhibitor only targets the non-CSC population in SUM149 cells. More interestingly, the resistant population expressed higher active Rad51 as measured for Rad51 foci formation. Our pervious study also showed that Rad51 mRNA level was significantly higher in ALDH+ cells of some breast cancer cell lines. Therefore, in this study, we established an inducible knock-down system using lentivirus and found that knocking down Rad51 sensitizes SUM159 (both CSC and non-CSC) as well as ALDH+ SUM149 cells to PARP inhibitor, suggesting the expression of Rad51 is associated with PARP inhibitor resistant population. This system was also tested in mouse model where cells carrying Rad51 shRNA were injected into the mammary fat pads of female NOD/SCID mice. Knock-down of Rad51 alone and combination treatment with PARP inhibitor dramatically inhibited tumor growth in the xenografts of both SUM149 and SUM159 cells, whereas, tumor grew back after Rad51 expression was restored. However the inhibitory effect remained in the combined treatment group after the treatment was terminated. Furthermore, the combination treatment decreased ALDH+ cells by IHC staining. It also showed a significant decrease in tumor-initiating cells in the combined treatment group by limiting dilution transplantation. Our results suggest that Rad51 plays an important role in resistance to PARP inhibitor in TNBCSCs thus Rad51 inhibitor may be a novel therapeutic approach in addition to PARP inhibition for treating TNBC pati