Diet is a modifiable factor associated with the risk of several cancers, with convincing evidence showing a link between diet and breast cancer. The role of bioactive compounds of food origin, including those found in cruciferous vegetables, is an active area of research in cancer chemoprevention. This review focuses on 3,3 0 -diindolylmethane (DIM), the major bioactive indole in crucifers. Research of the cancerpreventive activity of DIM has yielded basic mechanistic, animal, and human trial data. Further, this body of evidence is largely supported by observational studies. Bioactive DIM has demonstrated chemopreventive activity in all stages of breast cancer carcinogenesis. This review describes current evidence related to the metabolism and mechanisms of DIM involved in the prevention of breast cancer. Importantly, this review also focuses on current evidence from human observational and intervention trials that have contributed to a greater understanding of exposure estimates that will inform recommendations for DIM intake.

Purpose Diindolylmethane (DIM), a bioactive compound found in cruciferous vegetables, has proposed breast cancer chemoprevention activity. There is limited evidence of clinically relevant activity or long-term safety. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of DIM (BR-DIM) with tamoxifen. Methods Women prescribed tamoxifen (n=130) were assigned to receive BioResponse-DIM® (BR-DIM), providing 150 mgs DIM twice daily, or placebo, for 12 months. The primary study endpoint was change in urinary 2/16 -hydroxyestrone (2/16 -OHE1) ratio. Change in 4-hydroxyestrone (4-OHE1), serum estrogens and sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites also were assessed. Results Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. DIM increased the 2/16 -OHE1 ratio (+3.2[0.8, 8.4]) compared to placebo (−0.7 [−1.7, 0.8], p <0.001). Serum SHBG also increased with DIM as compared to placebo (+ 25±22 and +1.1 ±19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving DIM versus placebo (P <0.001). Minimal adverse events were reported and overall did not differ by treatment arm. Conclusion In patients taking tamoxifen for breast cancer, daily DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether decreases in tamoxifen metabolites, including endoxifen, with DIM would attenuate the clinical benefit of tamoxifen.

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