Abstract 3505: Energy restriction-mimetic agents (ERMAs) decrease BRCA1 expression levels in triple-negative breast cancer cells: A rationale for combining ERMAs with poly(ADP ribose) polymerase

Abstract

Abstract Purpose: Triple-negative (ER-negative, PR-negative, HER2/neu-negative) breast cancer (TNBC) is a clinical challenge because of the lack of a specific therapeutic target. Poly (ADP-ribose) polymerase (PARP)-1 is a nuclear enzyme involved in the detection and repair of DNA damage. In DNA repair-defective tumors, inhibition of PARP can cause genomic instability and cell death. Among the PARP inhibitors currently being assessed in clinical trials, recent results showed that, in a randomized phase II clinical trial of TNBC patients, BSI-201 when added to platinum-containing chemotherapy significantly improved the outcome of metastatic breast cancer patients relative to chemotherapy alone. Previously, we reported that the thiazolidinedione family of peroxisome proliferation-activated receptor-γ agonist could induce apoptosis in cancer cells by eliciting cellular responses indicative of energy restriction. Consequently, we used ciglitazone as a scaffold to develop novel energy restriction-mimetic agents (ERMAs) through structural optimization, which has yielded two lead compounds, CG-5 and CG-12. In prostate cancer cells, ERMAs could induce cell death and reduce the expression of BRCA1 protein. BRCA1 helps repair DNA double-stranded breaks through homologous recombination. BRCA1 deficiency has been reported to sensitize cells to PARP inhibition through synthetic lethality. We hypothesize that ERMAs can potentiate the anti-proliferative activity of PARP inhibitors (AZD-2281, AG-014699, ABT-888 and BSI-201) through the down-regulation of BRCA1 expression in TNBC cells. Methods: TNBC cell lines, MDA-MB-468, MDA-MB-231 and Cal-51 (all of which have functional BRCA1) were obtained from ATCC and DSMZ and maintained in low-glucose complete growth medium. Drug effects on cell viability were assessed by MTT assays. The expression of BRCA1, phosphorylated AMP-activated kinase (AMPK), and PARP cleavage in treated cells were examined by western blotting. Results: The ERMAs CG-5 and CG-12 exhibited dose-dependent anti-proliferative activity against all TNBC cell lines tested with IC50 values of about 3 and 4 μM, respectively, after 72 h of treatment. These anti-proliferative effects were attributed to apoptosis as both compounds induced the cleavage of PARP. Moreover, AMPK was activated by both drugs indicative of energy restriction. BRCA1 levels were reduced dose-dependently in all three TNBC cell lines after treatment with CG-5 or CG-12. Conclusion: The ERMAs CG-5 and CG-12 can reduce BRCA1 levels in TNBC cells. These findings provide a rationale for combining the ERMA-mediated ablation of BRCA1 with PARP inhibitors to induce TNBC cell death through synthetic lethality. Further study to address this hypothesis could lead to a new therapeutic approach for TNBC patients for whom available options are limited. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3505. doi:10.1158/1538-7445.AM2011-3505