Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Thomson, Cynthia A.; Ho, Emily; Ström, M.

doi:10.1093/nutrit/nuw010

Cited by 91 publications

(67 citation statements)

References 83 publications

(105 reference statements)

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“…This phenotype appeared specific to Chk2, as neither an ATR inhibitor(27) nor a Chk1 inhibitor(28) could induce endocrine treatment resistance (Fig 4e+f, Fig S6a+b). Moreover, ATM/Chk2 activation using the small molecule activator, 3,3′-diindolyl methane (DIM)(29) , (30) (validated in Fig S5e), rescued sensitivity of MCF7/MutL − (Fig S6c+e) and T47D/MLH1 − (Fig S6d+f) cells to endocrine treatment dose-dependently. These data suggest that Chk2 activation is both necessary and sufficient for MutL − induced endocrine therapy resistance.…”

Section: Resultsmentioning

confidence: 90%

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

et al. 2017

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Significant endocrine therapy-resistant tumor proliferation is present in ≥20% of estrogen receptor positive (ER+) primary breast cancers and is associated with disease recurrence and death. Here, we uncover a link between intrinsic endocrine therapy resistance and dysregulation of the MutL mismatch repair complex (MLH1/3, PMS1/2), and demonstrate a direct role for MutL complex loss in resistance to all classes of endocrine therapy. We find that MutL deficiency in ER+ breast cancer abrogates Chk2-mediated inhibition of CDK4, a prerequisite for endocrine therapy responsiveness. Consequently, CDK4/6 inhibitors (CDK4/6i) remain effective in MutL-defective ER+ breast cancer cells. These observations are supported by data from a clinical trial where a CDK4/6i was found to strongly inhibit AI-resistant proliferation of MutL-defective tumors. These data suggest that diagnostic markers of MutL deficiency could be used to direct adjuvant CDK4/6i to a population of breast cancer patients who exhibit marked resistance to the current standard of care.

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Section: Resultsmentioning

confidence: 90%

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

et al. 2017

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“…These mechanisms of action have been described in a recent review [10]. Important areas of bioactivity relevant to breast cancer chemoprevention include antioxidant effects, inhibition on COX-2 and other inflammatory response pathways [50].…”

Section: Discussionmentioning

confidence: 99%

“…Of these, 3,3′-diindolylmethane (DIM), a stable in vivo metabolite of indole-3-carbinol (I3C) found in cruciferous vegetables [9], is among the most well-studied [10]. We previously reported, from a secondary analysis, a 52% reduction in breast cancer recurrence among women consuming more cruciferous vegetables [11], hypothesized to be attributed to higher exposure to indolyl-3-carbinol and the related dimer, DIM [12,13].…”

Section: Introductionmentioning

confidence: 99%

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Thomson

Chow

Wertheim

et al. 2017

Breast Cancer Res Treat

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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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“…indole-3-carbinol and its condensation product 3,3'-diindolylmethane (DIM) have both been shown to be promising anti-tumour agents from Brassica vegetables [21,29,30].…”

Section: Temperature For Hydrolysis Of Indole-3-carbinolmentioning

confidence: 99%

Development of a Simple Method for Determination of Anti-cancer Component of Indole-3-carbinol in Cabbage and Broccoli

Li¹,

Wei²,

Li³

et al. 2017

JFNR

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Indole-3-carbinol is a potential anti-cancer agent, and it has been found rich in Brassica vegetables.However, there was few good extraction method of indole-3-carbinol in cabbage and broccoli. In this work, the wavelength and the ration of mobile phase in determination method, as well as different temperature and pH values in extraction method were all investigated some cultivars of cabbage and broccoli were collected and validated the determination method. A sensitive and rapid high-performance liquid chromatography method has been established and used for the determination of indole-3-carbinol in cabbage (Brassica oleracea L. var. capitata) and broccoli (Brassica oleracea L. var. italica). The method was proved to be sensitive, selective, rapid and reproducible, with a good recovery of 99.25%. There was a fast retention time (4.88 min) and good linearity (R 2 =0.9991) in the system. Meanwhile, significant differences of indole-3-carbinol contents were detected among all the materials (P<0.05). Finally a simple extracting method of indole-3-carbinol was established, at the same time, the determination method was shown accurate, reliable and stable. So the determination method could be proposed application in medical and industrial area.

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Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

Cited by 91 publications

References 83 publications

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

Loss of MutL Disrupts CHK2-Dependent Cell-Cycle Control through CDK4/6 to Promote Intrinsic Endocrine Therapy Resistance in Primary Breast Cancer

A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen

Development of a Simple Method for Determination of Anti-cancer Component of Indole-3-carbinol in Cabbage and Broccoli

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