Abstract 2539: The PARP inhibitor AZD2281 induces autophagy and complete cell death in BRCA mutant breast cancer cell lines

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 2539
• Main Authors: Akar, Ugur, Barrera, Angelica Gutierrez, Hortobagyi, Gabriel N, Arun, Banu
• Format: Journal Article
• Language: English
• Published: 15-04-2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-2539

BRCA1 and BRCA2 are well-known DNA repair proteins that are usually mutated or deleted in breast tumors. According to the literature, 5 (12%) of 41 breast cancer cell lines have BRCA mutations and 28 (68%) of the 41 cell lines have BRCA1 allelic loss. PARP inhibitors are known to inhibit tumor growth in BRCA mutant tumors. The purpose of this study was to investigate the effects of PARP inhibitors in BRCA mutant breast cancer cell lines. We found that AZD2281 as a single agent induced complete cell death in BRCA1 mutant (HCC-1937, MDA-MB-436, and SUM-149PT) and BRCA2 mutant (HCC-1428) cell lines. AZD2281 induced an average growth inhibition of 33% in BRCA wild-type cell lines with BRCA1 allelic loss. Downregulation of BRCA1 or BRCA2 by shRNA sensitized the triple-negative breast cancer cell lines BT-20 and MDA-MB-231 to AZD2281 treatment. We also investigated whether autophagy is induced in response to PARP inhibition. AZD2281 treatment induced LC3-II expression, an indication of autophagy. Transmission electron micrographs demonstrated autophagosome formation after AZD2281 treatment. On transmission electron micrographs, we observed a decrease in mitochondria related to autophagosome formation after AZD2281 treatment. To show AZD2281 induced autophagy is targeting mitochondria, we labeled mitochondria with yellow fluorescein protein using lentiviral stable transfection. Flow cytometry measurement demonstrated a decrease in fluorescein-labeled mitochondria after AZD2281 treatment. Inhibition of autophagy in a AZD2281-treated BRCA mutant breast cancer cell line rescued mitochondrial degradation and partially inhibited apoptosis. In conclusion, we showed that autophagy plays an important role in AZD2281-induced cell death in BRCA mutant breast cancer cell lines by degradation of mitochondria besides DNA degradation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2539. doi:1538-7445.AM2012-2539