Studies increasingly indicate that dietary
indole-3-carbinol (I3C) prevents the development of
estrogen-enhanced
cancers including breast, endometrial and
cervical cancers. Epidemiological, laboratory, animal and translational studies support the efficacy of I3C. Whereas
estrogen increases the growth and survival of
tumors, I3C causes growth arrest and increased apoptosis and ameliorates the effects of
estrogen. Our long-range goal is to best use I3C together with other nutrients to achieve maximum benefits for
cancer prevention. This study examines the possibility that induction of growth arrest in response to DNA damage (GADD) in genes by
diindolylmethane (DIM), which is the
acid-catalyzed condensation product of I3C, promotes metabolically stressed
cancer cells to undergo apoptosis. We evaluated whether
genistein, which is the major isoflavonoid in soy, would alter the ability of I3C/DIM to cause apoptosis and decrease expression driven by the
estrogen receptor (ER)-alpha. Expression of GADD was evaluated by real-time reverse transcription-polymerase chain reaction. Proliferation and apoptosis were measured by a mitochondrial function assay and by fluorescence-activated cell sorting analysis. The
luciferase reporter assay was used to specifically evaluate expression driven by ER-alpha. The
estrogen-sensitive MCF-7
breast cancer cell line was used for these studies. We show a synergistic effect of I3C and
genistein for induction of GADD expression, thus increasing apoptosis, and for decrease of expression driven by ER-alpha. Because of the synergistic effect of I3C and
genistein, the potential exists for prophylactic or therapeutic efficacy of lower concentrations of each
phytochemical when used in combination.