Abstract
Abstract Triple-negative breast tumors (TNBT) are associated with poor prognosis and high recurrence-rates after adjuvant therapy. Currently, there is no preferred standard form of chemotherapy for TNBT. Landmark studies on DNA damage checkpoints and associated repair function in preneoplastic and neoplastic cells have focused attention on the importance of the BRCA-RAD51 repair-pathway in the development and progression of TNBC. The PARP inhibitor (PARPi), Olaparib, is currently being tested in phase I / II trials in BC and holds promise for the treatment of BRCA-deficient basal-like and /or TNBC. PTEN protein/function is downregulated in ∼ 40% of breast cancer, including TNBT, and a recurrent gross-mutation of the PTEN gene is identified in breast cancer with deficient double-strand base-repair. We hypothesize that there is a cellular threshold for error-free DNA-repair in TNBT cells and that the absence of PTEN can sensitize these cells to a concurrent treatment of DNA-damaging agent (carboplatin) and PARPi (Olaparib). We determined: (a) the time course of expression of PAR protein following Olaparib in BRCA-incompetent TNBT cell lines, (b) enzymatic activity of PARPi in BRCA-competent MDA-MB-231(PTEN+), MDA468 (PTEN-null), and BT20, TNBT cells, (c) pro-apoptotic signals in both BRCA1-incompetent and BRCA1-competent TNBT cells, (d) anti-proliferative effect of Olaparib plus carboplatin on cell- survival (MTT assay, EC50s, automated live-cell counter), and 2D clonogenic assay. We have demonstrated: (1) a time dependent decrease in PAR expression with little alteration in the expression of total PARP within 24 hours of treatment of Olaparib in HCC1937 cells, (2) a comparable pattern of decrease in the levels of PAR expression in MDA-MB-231, MDA468, and BT20 cells following Olaparib and carboplatin at 24 and 48 hours, (3) a significant increase in the expression of cleaved-caspase 3 and 9, (4) a significant increase in the expression of cleaved-PARP, a downstream product of cleaved-caspase 3, (5) an increase in the TUNNEL-positive cells in response to Olaparib plus carboplatin and (6) a significant decrease in the percentage of cell-survival following combination-treatment. Strikingly, we found that amongst different BRCA-competent TNBT cells, PTEN-null MDA-MB468 cells appeared the most sensitive to the combination of Olaparib plus carboplatin with respect to EC50s, clonogenic assay, pro-apoptotic signals, and cell survival. Herein, we report a non-redundant function of PTEN in PARPi-mediated anti-proliferative and pro-apoptotic signals in TNBC. We are currently pursuing studies a) to delineate the mechanistic relationship between the thresholds of DNA repair and PTEN and b) to understand the phosphatase-independent role of PTEN in PARPi-mediated anti-proliferative / pro-apoptotic signals, the results of which will be presented in the meeting. 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 2935. doi:10.1158/1538-7445.AM2011-2935
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