Double strength orange juice given to the rats in place of drinking water inhibited mammary tumorigenesis induced in female Sprague-Dawley rats by DMBA more effectively than double strength grapefruit juice. This may mean that hesperetin retains its effectiveness in vivo better than naringenin, since the flavonoids are present in the juices at similar levels. It is also possible that orange juice contains other compounds that have anti-cancer activity and that may act synergistically with hesperetin. Citrus flavonoids are effective inhibitors of both estrogen receptor-negative MDA-MB-435 and estrogen receptor-positive MCF-7 human breast cancer cell in vitro. Furthermore, 1:1 combinations of flavonoids with tocotrienols and/or tamoxifen inhibit proliferation of the cells more effectively than the individual compounds. This synergism may be due to the fact that the compounds are exerting their inhibitory effects by different mechanisms.