The inhibition and treatment of breast cancer with poly (ADP-ribose) polymerase (PARP-1) inhibitors.
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.
De Soto
Joseph A
JA
Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA.
Wang
Xianyan
X
Tominaga
Yohei
Y
Wang
Rui-Hong
RH
Cao
Liu
L
Qiao
Wenhui
W
Li
Cuiling
C
Xu
Xiaoling
X
Skoumbourdis
Amanda P
AP
Prindiville
Sheila A
SA
Thomas
Craig J
CJ
Deng
Chu-Xia
CX
D000368:Aged; D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006801:Humans; D008408:Mastectomy; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics; D010052:Ovariectomy; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013234:Stem Cells / Q000187:drug effects; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1