Poly-ADP ribose polymerase (
PARP) inhibitors are effective for the treatment of BRCA-deficient
tumors. Women with these mutations have an increased risk of developing
breast cancer and would benefit from effective
chemoprevention. This study examines whether the
PARP inhibitors,
veliparib and
olaparib, delay mammary gland
tumor development in a BRCA1-deficient (BRCA1(Co/Co);MMTV-Cre;p53(+/-)) mouse model. In dose de-escalation studies, mice were fed with control,
veliparib (100 mg/kg diet), or
olaparib (200, 100, 50, or 25 mg/kg diet) continuously for up to 43 weeks. For intermittent dosing studies, mice cycled through
olaparib (200 mg/kg diet) for 2 weeks followed by a 4-week rest period on control diet. To examine
biomarkers, mice were fed with
olaparib using the intermittent dosing regimen and mammary glands were evaluated by immunohistochemistry. In mice treated with
veliparib or
olaparib (200 mg/kg diet), the average age of the first detectable
tumor was delayed by 2.4 and 6.5 weeks, respectively, compared with controls.
Olaparib also increased the average lifespan of mice by 7 weeks. In dose de-escalation studies, lower concentrations of
olaparib delayed
tumor development but were less effective than the highest dose. When fed intermittently,
olaparib delayed the onset of the first palpable
tumor by 5.7 weeks and significantly reduced proliferation and induced apoptosis in hyperplastic mammary glands. In summary,
veliparib and
olaparib are effective for delaying
tumor development and extending the lifespan of BRCA1-deficient mice, and intermittent dosing with
olaparib was as effective as continuous dosing. These results suggest that the use of
PARP inhibitors is a promising chemopreventive option.