Int J Biol Sci 2006 2:179-185 Copyright 2006 Ivyspring International Publisher.

http://www.biolsci.org/v02p0179

The Inhibition and Treatment of Breast Cancer with Poly (ADP-ribose) Polymerase (PARP-1) Inhibitors

Joseph A. De Soto1, Xianyan Wang1, Yohei Tominaga1, Rui-Hong Wang1, Liu Cao1, Wenhui Qiao1, Cuiling Li1, Xiaoling Xu1, Amanda P. Skoumbourdis2, Sheila A. Prindiville3, Craig J. Thomas2, Chu-Xia Deng1

1. Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
2. Chemical Biology Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
3. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10/9N105, 10 Center Drive, Bethesda, MD 20892, USA.


Abstract

BRCA1 and BRCA2 mutations are responsible for most familial breast carcinomas. Recent reports carried out in non-cancerous mouse BRCA1- or BRCA2-deficient embryonic stem (ES) cells, and hamster BRCA2-deficient cells have demonstrated that the targeted inhibition of poly(ADP-ribose) polymerase (PARP-1) kills BRCA mutant cells with high specificity. Although these studies bring hope for BRCA mutation carriers, the effectiveness of PARP-1 inhibitors for breast cancer remains elusive. Here we present the first in vivo demonstration of PARP-1 activity in BRCA1-deficient mammary tumors and describe the effects of PARP-1 inhibitors (AG14361, NU1025, and 3-aminobenzamide) on BRCA1-deficient ES cells, mouse and human breast cancer cells. AG14361 was highly selective for BRCA1-/- ES cells; however, NU1025 and 3-aminobenzamide were relatively non-selective. In allografts of nave ES BRCA1-/- cells there was either partial or complete remission of tumors. However, in allografts of mouse, BRCA1-/- mammary tumors, there was no tumor regression or remission although a partial inhibition of tumor growth was observed in both the BRCA1-/- and BRCA1+/+ allografts. In human tumor cells, PARP-1 inhibitors showed no difference in vitro in limiting the growth of mammary tumors irrespective of their BRCA1 status. These results suggest that PARP-1 inhibitors may non-specifically inhibit the growth of mammary tumors.

Keywords: PARP inhibitors, BRCA1, breast cancer, therapeutic treatment, tamoxifen