The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.

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 naïve 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.

• Authors: Joseph A De Soto, Xianyan Wang, Yohei Tominaga, Rui-Hong Wang, Liu Cao, Wenhui Qiao, Cuiling Li, Xiaoling Xu, Amanda P Skoumbourdis, Sheila A Prindiville, Craig J Thomas, Chu-Xia Deng
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 2 Issue 4 Pg. 179-85 ( 2006) ISSN: 1449-2288 [Electronic] Australia
• PMID: 16810332 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• BRCA1 Protein
• BRCA2 Protein
• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Aged
• Animals
• BRCA1 Protein (deficiency, genetics)
• BRCA2 Protein (deficiency, genetics)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Division
• Cricetinae
• Enzyme Inhibitors (therapeutic use)
• Female
• Genetic Carrier Screening
• Germ-Line Mutation
• Humans
• Mastectomy
• Mice
• Ovarian Neoplasms (genetics)
• Ovariectomy
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Stem Cells (drug effects)
• Transcription, Genetic
• Transplantation, Heterologous
• Transplantation, Homologous