Introduction

Cruciferous vegetables such as Brussels sprouts, broccoli, kale, cabbage, and cauliflower are rich sources of dietary bioactive compounds, namely, indole-3-carbinol (I3C) and its major metabolite 3,3ʹ-diindolylmethane (DIM). Chewing or chopping cruciferous vegetables results in the hydrolysis of the glucosinolate glucobrassicin into indole-3-carbinol catalyzed by the enzyme myrosinase.¹ Glucosinolate and myrosinase are stored intact in separate plant cell compartments and come together only after cell rupture. Under acid-catalyzed reaction conditions in the stomach, indole-3-carbinol degrades to several bioactive condensation products among the most known are 3,3ʹ-diindolylmethane (DIM) and indolo(3,2-b)carbazole (ICZ).^2–6 Other oligomers, namely, the cyclic trimer 5,6,11,12,17,18-hexahydrocyclonona(1,2-b:4,5-b’:7,8-b”)tri-indole (CTr), a cyclic tetramer CTet, the first linear trimer (LTr1), and the second linear trimer (LTr2).^2–4

Dietary consumption of cruciferous vegetables is associated with a variety of beneficial biological activities. It appears most of the I3C biological activities are result from its bioactive products, as I3C is virtually converted in the gut acidic environment.^2,3,7 Most of the biomedical research on indole-3-carbinol and 3,3ʹ-diindolylmethane were conducted using animals and human cultured cells. More than a thousand studies related to indole-3-carbinol and its major derivatives exposure on human cultured cells and animals have reported significant health benefits, such as chemo-prevention and therapeutic effects.

Indole-3-carbinol mainly its derivative 3,3ʹ-diindolylmethane has received considerable attention for having properties of anti-breast cancer,^8–10 anti-prostate cancer,^10–13 detoxification of toxicants,^14,15 induction of apoptosis,^16–18 prevent bone weakness^19–21 and anti-human papillomavirus.^22,23 Indole-3-carbinol and its major derivatives are the topics of ongoing research since 1975 when it was first reported that I3C increases the metabolism of carcinogenic chemicals.^24,25 Later on, several studies have shown that most of the biological activities of indole-3-carbinol are attributed to its condensation products. Among these, 3,3ʹ-diindolylmethane has been recognized as the major in vivo derivative responsible for most of the biological properties of indole-3-carbinol.^26–29

Epidemiological studies have shown that consumption of cruciferous vegetables significantly lowers the incidence of human cancer. An inverse association was found between high intake of cruciferous vegetables, particularly broccoli, and an incidence of breast cancer.³⁰ Higdon et al have reported that a high intake of cruciferous vegetables reduced the risk of human cancers in an epidemiological study.³¹ Studies using animal and human cultured cells have shown that 3,3ʹ-diindolylmethane inhibited the growth of a variety of cancer cells including prostate cancer,^32–37 breast cancer,^17,37-39 pancreatic cancer,^40,41 colorectal cancer,^42–46 lung tumors,^47,48 and nasopharyngeal cancer.^49,50 Other suggested roles of DIM include boosting immune function,^42,51,52 increase estrogen metabolism,⁵³ having anti-leishmaniasis^54–56 and anti-human papillomavirus properties^57–59 in animal and in vitro studies.

Although most of the published studies on DIM and its parent compound (I3C) were mainly in animal or in vitro models, there is an increasing media publicity advocating individuals to try I3C or DIM supplementation including formulation in drug form⁶⁰ for their potential applications in the prevention and treatment of diseases such as breast and prostate cancers. Recently, researchers and companies become more interested in the formulation of DIM as a supplement.⁶¹ This is because DIM has a greater stability compared to I3C after oral ingestion, where the latter virtually converted in the stomach acidic environment. Unlike DIM, there are warnings regarding the wide-spread use of I3C supplementation for cancer prevention and other roles until sufficient clinical data established regarding their potential risks and benefits.^62–67 The wide range of research outputs, marketing as a supplement, and other media publicity on I3C and DIM health benefits have evoked to review the existing human clinical-based literature in connection to DIM interventions. Therefore, the principal goal of this review was to review the human clinical trial published studies on DIM clinical efficacy towards prevention and treatment of diseases including the mechanism, and consistency of clinical trial scientific results. It also explores the nature of clinical-based studies in DIM intervention, adverse conditions/tolerability, and its bioavailability after direct oral supplementation. There is no comprehensive published review paper on human clinical trials from DIM supplementation.

Methods

Data Extraction and Synthesis

The extracted DIM supplementation information were about the study design, population demographics, form of DIM supplementation, dose and duration of DIM exposure, anti-cancer properties, other health effects, bioavailability of DIM, and safety/toxicity of DIM. Appraisal of methodological qualities of the studies was mainly weighted based on intervention time, sample size, and exposure dose.

Results and Discussion

Bioavailability of 3,3ʹ-Diindolylmethane in Human Clinical Trials

The pharmacokinetics of indole-3-carbinol and 3,3ʹ-diindolylmethane were studied in rodents. Oral administration of DIM to mice at the dose of 250 mg/kg has led to a rapid rise of plasma and tissues (brain, heart, liver, kidneys, and lungs) level between 0.5 to 1 h.⁶⁸ In another study, indole-3-carbinol administered to mice, it was rapidly absorbed, distributed, and eliminated in the blood and body tissues, falling below the detection limit after 1 h² whilst DIM was substantially detected in the blood and tissue samples which persists after 24 h.²

Oral administration of indole-3-carbinol to human subjects has shown that DIM is the major product detected in plasma samples relatively with a longer half-life.^2,69 This showed that following ingestion of indole-3-carbinol, the formation of the major derivative product DIM and the several reported biological activities has led to the study of DIM as a possible chemopreventive and therapeutic supplement. Besides the several suggested biological benefits of DIM, it has an important role as a biomarker for indole-3-carbinol or cruciferous vegetable consumption.

Herein, the focus was on the primary end-points of DIM (plasma, urine, and/or tissues) resulting from BR-DIM supplementation to human subjects. It has been reported that DIM was the only product detected in plasma samples after non-smoking women subjects (n=24; age between 23 and 58 years) with an elevated risk of breast cancer (by family history) ingested at oral doses of 400, 600, 800, 1000, and 1200 mg indole-3-carbinol.⁷² As Reed et al reported, the maximum plasma concentration (C_max) of DIM in the women was detected at 1000 mg I3C oral dose.⁷² In another study with a principal objective to quantify DIM in urine samples of women with cervical dysplasia after ingesting I3C resulted in a mean value of DIM, 12.1 ± 2.5⁷³ and 15.6 ± 22.2⁷³ μg/mg creatinine for the 200 and 400 mg DIM exposed groups, respectively.⁶⁹

Two randomized human clinical trials were also performed with the primary purpose of quantifying DIM in urine after twenty-five (healthy, non-vegetarian, and non-smoking) adults’ consumed raw cruciferous vegetables (Brussels sprouts and cabbage).^74,75 Fujioka et al⁷⁴ revealed that urinary DIM was successfully quantified with higher quantity in Brussels sprout than cabbage after 25 subjects (10 males and 15 females who were healthy, non-vegetarian, non-smoking; ages 22 to 63 years) ingesting 50 g of these raw vegetables per day for 3 days. Fujioka et al⁷⁵ demonstrated that urinary DIM increased with increasing glucobrassicin dose after the 45 subjects (19 males and 26 females, age 18 to 60 years) consumed cruciferous vegetables (with exposure doses of glucobrassicin at 25, 50, 100, 200, 300, 400 or 500 μmol). These authors claimed that the majority of DIM was eliminated in urine in the first 12 h of the intervention. In prostate cancer patients (n=45; mean age of 61.1 years), the mean value of DIM level in plasma samples was reported as 4.95±17.6, 151.42±197.1, and 280.4±217.2 ng/mL for placebo, 200 mg, and 400 mg/day BR-DIM doses, respectively, after 2 weeks of intervention period.⁷⁶ Rajoria et al reported that the mean value of DIM in urine, serum, and thyroid tissues was 383.5 ng/mg of creatinine, 12.32 ng/mg of creatinine, and 40.67 ng/mg tissue, respectively, after seven women patients (between ages of 39–56 years) with thyroid proliferative disease ingested 300 mg of BR-DIM per day for 2 weeks.⁷⁷ Reed et al depicted a dose-dependent DIM concentration in plasma samples of 24 healthy subjects (13 Men and 11 Women; ages 22 to 58 years) who consumed a single dose of BR-DIM at the doses of 50, 100, 150, 200 or 300 mg. These authors reported that DIM C_max in plasma was reached at 200 mg dosage. Similarly, Heath et al have reported that BR-DIM (at the doses of 75, 150, 225, and 300 mg twice daily) supplementation to 12 prostate cancer patients resulted in rapid absorption of DIM between 2 and 4 h, and dose-proportional plasma levels.⁷⁸ Another study has shown that the mean value of DIM in prostate tissue and plasma was 14.2 ng/gm tissue and 9.0 g/mL, respectively, in 36 prostate cancer patients who ingested 225 mg of BR-DIM twice daily for 2 weeks.⁷⁹

DIM Supplementation and Cancer: Human Clinical Trials

The completed human clinical studies mainly focused on breast or prostate cancer patients. Besides the suggested benefits of DIM in breast and prostate cancer prevention and treatment, similar studies in animal and human cultured cells have shown the role of DIM to inhibit growth of a variety of cancer cells, namely, pancreatic cancer,^40,41 colorectal cancer,^42–46 lung tumors,^47,48 and nasopharyngeal cancer.^49,50 However, there was no single human clinical trial study conducted to establish an association between DIM supplementation, and pancreatic, colorectal, lung, or nasopharyngeal cancer. Hence, the discussion under this section emphasized on clinical trial studies that involved DIM supplementation and endpoints mainly in either healthy subjects, breast, or prostate cancer patients.

Breast Cancer

Many studies in animals and in-vitro including epidemiological have shown that 3,3ʹ-diindolylmethane modulate the endogenous estrogen hormone playing a role in the prevention and inhibition of growth of estrogen-dependent breast cancer including endometrial and cervical cancers.^80–82 The human estrogen receptor becomes a crucial target of chemo-preventive and therapeutic strategies to control the estrogen-dependent proliferation of breast cancers. Thus, 3,3ʹ-diindolylmethane agonist to the human estrogen receptor has been related to having beneficial effects to treat menopausal complaints, steroids and lipid metabolism, prevent bone loss, and improve sexual problems in females.^19,83-86 DIM has induced the cyochromp450 enzymes specifically, by up-regulating the CYP1A1, CYP1A2, and CYP1B1 enzymes^87,88 to catalyze the human estrogen metabolism.

It has been shown that DIM promotes the metabolism of the estrogen hormone by increasing the beneficial estrogen metabolite, namely 2-hydroxyestrone over the unfavorable 16-alpha-hydroxyestrone.^28,89 The endogenous estrogen (17β-estradiol), the primary female sex hormone, metabolized to 16α-OHE1 or 2-OHE1. Unlike 2-OHE1, the 16α-OHE1 metabolite has strong estrogenic properties, and highly associated to promote the proliferation of estrogenic dependent breast cancer.^90,91 Previous researches suggested that changing the course of the 17β-estradiol metabolism towards 2-OHE1, and suppressing the 16α-OHE1 may have a role to reduce the incidence of estrogen-based cancers including breast cancer^89,92,93 although other studies found no association.^94,95 Several studies in animals and cultured cells including epidemiological have depicted that the dietary compound DIM modulates the endogenous estrogens consequently playing a role in the suppression of growth of estrogen-dependent cancers.^80–82

In light of that supplementation of DIM in human clinical trial studies and its efficacy towards prevention or treatment of estrogen-dependent cancers has been discussed in this section.

Supplementation of BR-DIM to humans has significantly increased the ratio of 2-OHE1 to 16α-OHE1^28,76,96,97 whilst Nikitina et al⁹⁸ reported no change in the ratio of the two estrogen metabolites (see the summary in Table 1). Dalessandri et al have found that BR-DIM supplementation (108 mg/day for 30 days) increased the ratio of 2-OHE1 to 16α-OHE1 (from 1.46 to 2.14) in a double-blind randomized controlled trial (10 in the treatment group and 9 in the placebo) in women (aged 50–70 years) with a history of early stage breast cancer.²⁸ Similarly, Gee et al have reported a significant increase in urinary 2-OHE1 to 16α-OHE1 ratio in the BR-DIM (at 100 or 200 mg or placebo twice daily for 21–28 days) exposed group in a double-blind randomized controlled trial in 45 patients with prostate cancer.⁷⁶ Through another molecular path-way, BR-DIM (300 mg per day for 4–6 weeks) supplementation to 13 women (with a tumor suppression BRCA1 gene carriers) has resulted in the up-regulation of BRCA1 (breast cancer type 1) gene expression in the 10 subjects.⁹⁹ The increase in BRCA1 gene expression is associated with breast cancer prevention or suppression of tumor proliferation.^100–103

Overall, DIM supplementation in the aforementioned clinical trials showed its effect in increasing endogenous estrogen hormone metabolism, and the ability to induce BRCA1 gene expression, where both biological activities have been linked to having beneficial effects in the prevention of estrogens-dependent cancers. Although epidemiological studies supported cruciferous vegetables consumption and a role in lowering risks of breast cancer among women,^30,31 there lacks single clinical trial study that directly indicated DIM supplementation and its efficacy towards treatment of breast cancer or other estrogen-dependent cancer in the studied subjects. Given the insufficient intervention time (the maximum was 12 months), the author recommends larger cohort studies in future clinical trials to see DIM efficacy in preventing the incidence of estrogen-dependent cancers in healthy subjects or its therapeutic effect for women with breast patients.

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Prostate Cancer

Several studies have revealed that 3,3ʹ-diindolylmethane has a potent anti-androgenic property mediated by the human androgen receptor that renders important benefits in preventing and reducing the proliferation of androgen-based prostate cancer cells.^29,37,82,104 The antagonist properties of 3,3ʹ-diindolylmethane to androgen hormone at the receptor level have useful chemopreventive properties for prostate cancer.^29,105 There are studies that supported the role of 3,3ʹ-diindolylmethane in prostate tumor growth suppression via non-receptor pathways.^{11,18,32,34,106}

Some epidemiological studies have supported that consumption of cruciferous vegetables associated with lower risks of prostate cancer.^107–110 On the other hand, there are studies that found statistically non-significant between consumption of cruciferous vegetables and risk of prostate cancer inverse association.^111–114

The remaining discussion in this section focused on human clinical trial studies that have linked DIM supplementation and its effect on a number of molecular targets, believed to be beneficial for therapeutic or chemoprevention purposes related to prostate cancer. Kong et al have reported that BR-DIM (300 mg per day for 4–6 weeks) supplementation to prostate cancer patients (age between 47 and 64) resulted in the up-regulation of let-7, which is a family of microRNAs.¹¹⁵ Down-regulation of the let-7 family has been associated with promoting the recurrence and elevation of prostate cancer by regulating cancer stem cells.¹¹⁶ Previous research conducted on BR-DIM (four cohorts exposed to doses either 75, 150, 225, or 300 mg twice daily for 4 months) supplementation has resulted a decrease in prostate-specific antigen among the 10 subjects (n=13) even though the conditions eventually progressed.⁷⁸ Men with elevated level of prostate-specific antigen are at the greatest risk to develop prostate cancer^117–119 and hence the reduction of this antigen by DIM may have a role in combating tumor formation in prostate tissues.⁷⁹ A study has shown that prostate cancer patients (n=36) who ingested DIM (at 225 mg twice daily for 2 weeks) resulted in the exclusion of the androgen receptor from the cell nucleus in the 27 (96%) of patients, and prostate-specific antigen decline in the 20 (71%) of patients.⁷⁸ These human clinical trial studies have shown that DIM is a promising bioactive compound to modulate molecular targets, responsible for the initiation and progression of prostate cancer. Even though several animals and laboratory studies^{18,32-34,37,120,121} and some epidemiological studies^107–110 depicted DIM ability to exert apoptosis and arrest proliferation in prostate cancer cells, no single clinical trial study has shown DIM efficacy towards prevention and treatment of prostate cancer. Therefore, larger prospective cohort clinical trials are recommended in future interventions to establish an inverse relation between DIM supplementation and the formation or proliferation of prostate cancer.

Anti-Viral and Anti-Dysplasia Effects: Human Clinical Trials

The human papillomavirus is an important risk determinant for the development of cervical/vaginal intraepithelial neoplasia and cervical cancer.^122–126

In a double-blind randomized control trial, BR-DIM (45 DIM vs 19 placebo, 2 mg/kg body-weight for 3 months) supplementation to 64 women (mean age 28 years, range 18–61) with cervical intraepithelial neoplasia showed that 21 subjects (47%) in the treatment group improved their condition with a decrease by 1–2 grades.¹²⁷ DIM (at the dose of 100, 200 mg/day or placebo for 90–180 days) intervention in 78 women (age between 19 and 39 years) with cervical intraepithelial neoplasia grade I–II resulted in regression of their conditions as reported 100%, 98.83%, and 61.1% of subjects for the high dose, low dose, and placebo, respectively.⁶⁰

Paltsev et al investigated the Infemin (a formulated DIM at a dose of 900 mg daily or placebo for 3 months) supplementation effect in 14 patients (ages 18 to 60 years) with prostatic intraepithelial neoplasia and found out that clinically non-significant improvement in their conditions.¹²⁸ Paltsev et al, however, continued a second-round double-blind randomized placebo-controlled multicenter clinical trial among 21 patients (11 received Infemin 900 mg vs 10 placeboes per day for 12 months) diagnosed with a high-grade prostatic intraepithelial neoplasia which resulted in a complete reversion of the 45.5% subjects condition.¹²⁹ This marked difference in the clinical effect compared to the first round trial is apparently related to the extended intervention duration.

On the other hand, previous research on BR-DIM supplementation (150 mg or placebo for 6 months) to 551 women (age range 19–65 years) with human papilloma-virus and low-grade cervical cytological abnormalities showed no effect on cervical cytology or on HPV infection.¹³⁰ Similarly, DIM (150 mg or placebo for 6 months) supplementation to 84 women diagnosed with low-grade cervical neoplasia and infected with HPV has resulted in statistically non-significant (only 11 subjects negative) clinical efficacy.

Although these clinical trial results are promising about the clinical efficacy of DIM to treat cervical or prostatic intraepithelial neoplasia, longer prospective cohort clinical studies may strongly support whether this dietary compound is clinically efficient to treat various cases of dysplasia.

Adverse Effects

Systemic toxicity was not observed in all of the human clinical trial studies after ingestion of DIM. Adverse health effects were not reported when 18 healthy men and women were supplemented with BR-DIM between 50 and 200 mg dose.¹³¹ When the dose was increased to 300 mg, however, one subject reported headache and nausea, and another subject reported vomiting. Reed et al have increased the BR-DIM dosage (1200 mg per day for 2 months) to healthy women (n=20) and subsequently, 5 women reported short-term gastrointestinal distress which seemed to be dose-dependent.⁷²

Another study has reported that 49 women with cervical dysplasia were exposed to BR-DIM at the dose of 2 mg/kg/day for 3 months, and the dose was well tolerated with no systemic toxicity.¹²⁷ DIM oral ingestion by all subjects was well tolerated, if any, short-term gastrointestinal distress, nausea, and vomiting were adverse effects reported but in most cases were statistically non-significant.

Limitations to the Human Clinical Trials

Most of the clinical trials focused on the determination of endpoints of DIM supplementation in human subjects. With prostate or breast cancer patients, most of the trials were merely to see DIM effect on estrogen hormone metabolism, prostate-specific antigen, or DIM plasma/urine/tissue level (Table 1). In other words, there was no single human clinical study primarily conducted to show therapeutic effect of DIM in prostate or breast cancer patients. Similarly, no single study among the pooled human clinical researches did show DIM’s (as chemopreventive) ability to impede development of cancer in healthy subjects. The major weakness of these clinical trials, in particular with prostate or breast patients was the intervention period. For prostate cancer patients the maximum DIM intervention time was 28 days⁷⁸ while the minimum reported time was 2 weeks.²⁸ The minimum and maximum DIM intervention period for the breast cancer patients were 4 weeks and 12 months, respectively,^97,98 though the latter intervention was in combination with tamoxifen. For the combined intervention, the authors reported that no change in breast cell density observed in all subjects but did not disclose if treatment occurred. Therefore, the intervention time for future clinical trials should be sufficiently long for prostate and breast cancer patients or chemoprevention in healthy subjects. Paltsev et al have found initially clinically non-significant improvement in the prostatic intraepithelial neoplasia patients in the 3 months of DIM intervention,¹²⁸ however, Paltsev et al increased the exposure period to 1 year with the same DIM dosage and it turned out that the 45.5% subjects showed a complete reversion in their condition.¹²⁹

Conclusion and Recommendations

Several animal and human cultured cells on DIM supplementation and its effect on estrogen metabolism were consistent with the human clinical trials. DIM intervention in the human clinical trials has shown its efficacy in regulating some molecular targets responsible to induce tumor formation. This suggests that DIM can be a promising chemopreventive supplement. Among the pooled clinical trials, no single study established a research to directly see DIM’s efficacy in treating breast or prostate cancer. The absence of clinical evidence about DIM efficacy to treat prostate or breast cancer is found to be the major concern as this dietary compound is being sold on the market as a supplement for treatment in these disease conditions.

Several clinical trial studies have shown that an absorption-enhanced formulation of DIM (BioResponse-DIM) displayed 50% greater bioavailability than the crystalline form after oral ingestion.

The maximum DIM intervention time for breast and prostate cancer patients was 28 days and 12 months, respectively. Therefore, it is recommended that future larger prospective clinical trial research with substantial intervention time is required to see DIM’s ability to treat breast, prostate, and other cancer cases. Moreover, much of the completed clinical researches have focused on the lonely effect of DIM as a therapeutic or chemopreventive agent.

— Update: 15-02-2023 — cohaitungchi.com found an additional article 3,3-Diindolylmethane (DIM): a nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial from the website academic.oup.com for the keyword dim breast cancer.

Abstract

Introduction

Women who carry the BRCA gene mutation are at high risk of the development of breast cancer, reaching 80% over their lifetime (1,2). Currently, there is no consensus regarding an effective and safe chemoprevention strategy. Therefore, in addition to active surveillance, BRCA mutation carriers are referred for bilateral salpingo-oophorectomy and instructed to consider bilateral mastectomy as a risk-reduction strategy (3).

There is a large body of evidence suggesting that 3,3-diindolylmethane (DIM), a dimer of indole-3-carbinol found in cruciferous vegetables, can potentially prevent carcinogenesis, tumor development (4–7) and shift estrogen metabolism in healthy postmenopausal women (8). Estrogen metabolism plays a causative role in breast cancer (9–11). The ovaries produce estrogen in the form of the parent molecules estrone and estradiol, which can be irreversibly hydroxylated via various pathways (12–15). Hydroxylation at the C-2, C-4 or C-16 positions of the steroid ring produces estrogen metabolites that differ in their bioavailability to breast tissues and activation of estrogen receptors. Numerous studies have shown that the ratio between the different metabolites is correlated with the risk of breast cancer (12–15). For example, more extensive 2-hydroxylation of the parent estrogens (2:16 ratio) is associated with a lower risk of breast cancer, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with a higher risk of breast cancer (10). Moreover, several studies showed that DIM induces apoptosis in cancer cells and prevents the development of cancer in animal models (16–18). These findings, also confirmed by others (19–22), support the rationale for investigating the use of DIM to prevent breast cancer development or recurrence. Some studies suggested possible other benefits in BRCA carriers (23,24).

Breast density is a well-established surrogate for predicting the risk of breast cancer (25–27). The pivotal preventive trial, NSABP–P1, revealed that among the women in the tamoxifen arm, a decrease in mammographic density by at least 10% was associated with a 63% reduction in breast cancer risk, whereas a lesser decrease in density was not beneficial (28). Later studies showed that breast density could also be measured on magnetic resonance imaging (MRI) scans by the amount of fibroglandular tissue (FGT) and background parenchymal enhancement (BPE), the matching definition to mammogram breast density. An increase in these factors is associated with a higher probability of the development of breast cancer (29,30). The aim of the present study was to investigate the impact of 1 year of DIM supplementation on MRI breast density and estrogen metabolism in healthy BRCA carriers. We sought to determine the potential of DIM as an effective and safe strategy to decrease the risk of the development of breast cancer.

Setting and women

Dalessandri et al. reported that DIM supplementation at a dose of 108 mg/day for 30 days increased urinary 2-hydroxyestrone excretions in postmenopausal women with a history of breast cancer (22). Pharmacokinetics data demonstrated a linear dose–exposure relationship for DIM over the range of 50–300 mg. Doses of DIM of up to 200 mg were well tolerated by healthy subjects. The dosage was set to 100 mg × 1 daily to represent the best bioavailability with the least reported side effects. (31)

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The DIM dietary supplement (DIM-Evail^TM) was donated by Designs for Health (Suffield, CT). Each softgel capsule contained 100 mg diindolymethane and the additional ingredients were medium chain triglycerides, vitamin E, sunflower lecithin; gelatin, purified water, glycerin and annatto (softgel ingredients). The company did not have any access to women or data. The study was approved by the local Institutional Ethics Committee (ClinicalTrials.gov Identifier: NCT02197000).

Study endpoints

Primary endpoint

The primary endpoint of the study was a change in MRI breast FGT amount and BPE measurements from before to after 1 year of daily oral supplementation with 100 mg × 1/day DIM. The primary outcome was assessed using the BI-RADS (see MRI technique). The MRI scans of the matched DIM-untreated women attending the clinic in a parallel year were evaluated for the same primary endpoints.

Secondary endpoints

The secondary endpoints of the study were a change in urinary estrogen metabolism and serum hormone profile from before to after 1 year of DIM supplementation, side effects of DIM and malignancy events during the intervention.

Biomarker measurement

Participants were tested using the 0142 Estronex^® Profile kit (Metametrix, Duluth, GA) at study initiation and again after 1 year. The first morning urine was collected. Premenopausal women were instructed to perform urine collection on days 18–25 of the menstrual cycle; follow-up testing was performed on corresponding days of the cycle. Samples were shipped to Genova Diagnostics (Duluth, GA) and analyzed for six urine estrogen metabolites based on the ultra performance liquid chromatography tandem mass spectrometry method as follows: 2-hydroxyestrone, 2-hydroxyestradiol, 4-hydroxyestrone, 16a-hydroxyestrone, 2-methoxyestrone and 4-methoxyestrone. The test report also provided the results for 2-hydroxyestrone+ 2-hydroxyestradiol, 2/16 hydroxyestrogen ratio and 2-hydroxyestrone/2-methoxyestrone.

The serum hormone profile was assessed at the laboratory in Rabin Medical Center at study initiation and after 1 year. The analysis included levels of follicle-stimulating hormone, luteinizing hormone, estradiol, progesterone, prolactin, testosterone, sex hormone-binding globulin and thyroid-stimulating hormone.

MRI technique

We performed breast MRI at baseline and after 1 year of DIM supplementation. Imaging was conducted according to the guidelines of the National Comprehensive Cancer Network/American Society of Clinical Oncology.

Breast MRI was carried out with a 3T or 1.5T machine (3T Ingenia and 1.5T Achieva, Philips Medical Systems, Best, Netherlands). Women were examined in the prone position using a bilateral, 16-channel breast coil (Mammotrak, Philips Medical Systems). Initially, an axial T2w turbo spin-echo (TSE) sequence was used for both field strengths, with echo time (TE) 120 ms, in-plane resolution 1 mm and slice width 3 mm with zero gap. This was followed by a T2w TSE sequence with SPAIR fat suppression. For 3T imaging, a 2D sequence was used with the same resolution and TE 70 ms. At 1.5T, a 3D Vista sequence was used with repetition time/TE 2000/280 ms, in-plane resolution 0.8 mm and slice width 2 mm reconstructed to 1 mm. The dynamic 3D sequence with SPAIR fat suppression was performed using six dynamics with approximately 64 s per dynamic for both field strengths. At 3T, the flip angle was 12° with repetition time/TE 6.3/3.0 ms, in-plane resolution 0.8 mm and slice width 1.8 mm reconstructed to 0.9 mm. At 1.5T, the flip angle was 10° with repetition time/TE 6.6/3.2 ms, in-plane resolution 1.2 mm and slice width 1.8 mm reconstructed to 0.9 mm.

Qualitative FGT amount and BPE were assessed on the MRI images by two fellowship-trained radiologists with a specialty in breast imaging (A.G. and Y.R.) who were blinded to each other’s report, as well as to the timing of the test in relation to the DIM intervention. The amount of FTG was scored in accordance with the BI-RADS categories as follows: (i) almost entirely fat, (ii) scattered areas of FGT, (iii) heterogeneous FGT or (iv) extreme FGT amount. The BPE findings were reviewed on the basis of the amount of FGT enhancement on the first postcontrast images and categorized, in accordance with the BI-RADS, as (i) minimal, (ii) mild, (iii) moderate or (iv) marked. Subtraction and maximum intensity projection images were created by subtracting the unenhanced T1-weighted image from the initial contrast-enhanced image. In cases of substantial patient motion between examinations, BPE was determined by visual comparison of the initial unenhanced and contrast-enhanced images (32). In premenopausal women, MRI was performed on the recommended days 7–15 of the cycle.

Follow-up

Women were asked to report all side effects immediately. During the study period, women were contacted by phone once a month to verify that indeed all side effects were reported and to check adherence. Physical examination was performed at the clinic every 4 months. Breast imaging was repeated annually.

Statistical analysis

Since each woman served as her own control, we performed a per-protocol analysis for those who completed the study. Matched t-test was used to compare mean BI-RADS scores of FGT amount and BPE from before to after 1 year of DIM supplementation. The type I error probability associated with this test of the null hypothesis was set at 0.05.

The data of the matched clinic women were used for the sensitivity analysis. Differences in hormone profile from before to after treatment were tested using Fisher’s exact test. SAS version 9.2 was used for all analyses.

Results

Patient characteristics

Of the 52 women who were assessed for eligibility for the study, 40 signed the informed consent form. Twenty-three women completed 1 year of intervention. The CONSORT flow diagram in Figure 1 depicts the selection of the final cohort for the study.

Median age of the study group was 47.1 years (range: 35–71.3). Eighteen women carried the BRCA1 mutation, and five women carried the BRCA2 mutation. Eighteen women (78%) were postmenopausal at study onset, of whom three were using hormone replacement therapy (HRT) during the study period. The patient characteristics, including comorbidities and risk factors, are summarized in Table 1.

Primary outcome

The average BI-RADS score for the amount of FGT decreased during the DIM intervention from 2.80 ± 0.8 to 2.65 ± 0.84, P = 0.031 (Table 2). FGT amount decreased by 0.6 in 30% of women. The three women receiving HRT showed no change in breast tissue density. In no woman was there an increase in density. Figure 2 shows MRI imagings before and after 1 year of intervention.

There was no statistically significant change in BPE scores from before to after completion of the intervention (1.3 ± 5.7 versus 1.3 ± 1.73, P = 0.43; Table 3). Two women showed an increase in BPE scores.

The matched group showed no significant difference in FGT amount: 2.28 ± 0.9 and 2.3 ± 0.89 after 1 year (P = 0.33) or in BPE score: 1.48 ± 0.66 versus 1.5 ± 0.6 (P = 0.81) after a year of follow-up. Inter-rater agreement (kappa value) between the two radiologists was 0.82 for density and 0.814 for BPE.

Secondary outcome

Mean estradiol level of the study group decreased from 159 ± 116 to 102 ± 29 pmol/l (P = 0.03), and mean testosterone level decreased from 0.42 ± 0.37 to 0.31 ± 0.26 pmol/l (P = 0.03). No significant changes were seen in levels of follicle-stimulating hormone, luteinizing hormone, progesterone, prolactin, sex hormone-binding globulin or thyroid-stimulating hormone. There were no significant changes in any of the urine metabolites evaluated.

Side effects

Three women reported a change in bowel movements. Four women complained of headache and one had nausea. In one patient with known atopic dermatitis, erythema developed which required treatment with systemic steroids. All side effects were grade 1.

Malignancy events

One patient was diagnosed with node-negative invasive breast cancer (7 mm) at age 58 years, 5 months after starting DIM. A review of her previous MRI revealed a nonspecific 3-mm focus, which was interpreted as benign. One patient aged 44 years was referred for prophylactic oophorectomy and was diagnosed with stage I ovarian cancer at 16 months after starting DIM.

Discussion

This is the first study to prospectively examine the impact of DIM (100 mg × 1/day) on the amount of FGT and BPE on breast MRI in BRCA carriers. The results showed a significant reduction in the amount of FGT after 1 year of the intervention, with no change in BPE. In addition, mean estrogen and testosterone levels decreased. No safety issues were encountered, and all side effects were grade 1.

By contrast, a previous randomized, placebo-controlled trial in 98 tamoxifen-treated patients with breast cancer reported no impact of DIM on breast density measured on both mammograms and MRI scans (33). However, there are several differences between this study and ours. Our cohort consisted of women with no history of breast cancer, whereas the earlier study investigated DIM as a secondary preventive measure in patients with breast cancer. The authors did not mention if any of the patients was a BRCA carrier. Moreover, in the present study, DIM was the only intervention, whereas in the randomized study, all patients were also receiving tamoxifen, so the impact of DIM could not be isolated. Lastly, breast density was the primary endpoint in our study but the secondary endpoint in the earlier study.

Little is known about DIM and its effect on BRCA carriers.

Kostopauolos et al. (23) followed healthy BRCA1 carriers taking DIM for 4–6 weeks. An increased level of messenger RNA was noted, which the authors suggested could mitigate the deleterious effect of the BRCA mutation. Fan et al. (24) suggested that low concentrations of DIM protected against oxidative stress in BRCA1 carriers.

Others reported an impact of DIM on urinary estrogen metabolites (20,21). This was not shown in our study, perhaps owing to the low DIM dose (100 mg × 1/day). Our results are in accordance with the study of Nikitina et al. (34), wherein 4–6 weeks of DIM 300 mg/day in 15 BRCA carriers had no effect on urinary 2:16 hydroxyestrogen ratio.

Most of the literature to date on breast density was based on mammography. As some of the BRCA carriers in our clinic were too young for screening mammography, we used FGT amount and BPE on MRI scans as the primary endpoints. In this manner, we could offer participation in the study to all BRCA carriers in the clinic, regardless of age. This approach was supported by studies showing substantial agreement between automated volumetric FGT measured from screening digital mammograms and from MRI scans, suggesting that MRI could be used in clinical practice for risk prediction and prevention (35–37). One study of the effect of lifestyle changes prospectively assigned BI-RADS breast density scores to 301 955 women aged 30 years and older who were not on postmenopausal HRT (38). At least two screening mammography examinations were performed in each case. The results showed an increase in breast density category in 19.6% of the cohort. Although these authors assessed the breast density changes over time using mammography, it is still interesting to note the difference from our study in which none of the women taking DIM showed an increase in the FGT amount. A smaller study used 3D MRI to evaluate breast density in 16 tamoxifen-treated women (39). After 2 years, there was a mean reduction of 5.8% in the percentage of breast density, which positively correlated with the baseline percentage of breast density, supporting the use of MRI to assess breast density during systemic treatment.

There are other factors that may impact breast density, such as day of the menstrual cycle, alcohol consumption and use of HRT. In the present study, there were no changes in the women’s habits during the intervention. Most had undergone bilateral salpingo-oophorectomy and, in those who were still premenopausal, MRI was performed on the recommended days 7–15 of the cycle. Hence, the most dominant known factor that may have impacted the FGT amount was the 1-year increase in age (27). It is noteworthy that none of the three women in our cohort who used HRT showed a decrease in the amount of FGT.

Although the decline observed in blood estradiol and testosterone levels may be part of aging (40), and the difference from before the intervention was statistically significant, the level of decline was probably insufficient to impact FGT amount. In conclusion, our results suggest that DIM supplement may have a potential role in the primary prevention of breast cancer in healthy BRCA carriers.

The main limitations of this study were the nonrandomized design, 1-year duration of the intervention in a lifetime relative high-risk cohort, the relatively small sample size and the higher FGT/BPE baseline values in the matched clinic women. However, each woman served as her own control which made it possible to achieve statistically valid results despite the small number of women. The comparison with the matched women supports the potential of DIM intervention to have a real impact on breast density. In addition, two highly experienced radiologists separately examined the MRI scans, with similar results.

In summary, the need of healthy BRCA carriers for a safe and effective means of preventing breast cancer is currently unmet. The present study showed that the administration of DIM capsules, 100 mg × 1/day, to BRCA carriers led to a significant decline in the FGT amount on MRI scans. These findings, together with the accumulating data on the potential anticancer effect of DIM in the general population and in individuals with different genetic mutations (23,41), justify further investigations in randomized clinical studies of the primary preventive role of DIM supplementation in women with BRCA mutations.

Read more  3,3-Diindolylmethane (DIM): a nutritional intervention and its impact on breast density in healthy BRCA carriers. A prospective clinical trial

Funding

The study was partially sponsored by the Israel Cancer Association (grant no. 20161385).

Abbreviations

Acknowledgements

The DIM supplement used in the study was contributed by Designs for Health, Inc. The company received no information on the study participants.

Conflict of Interest Statement: None declared.

References

Author notes

— Update: 15-02-2023 — cohaitungchi.com found an additional article I3C & DIM: Adjunctive Therapy for Breast Cancer Patients on Tamoxifen from the website ndnr.com for the keyword dim breast cancer.

 

I3C & DIM: Adjunctive Therapy for Breast Cancer Patients on Tamoxifen

Student Scholarship – Third Place Research Review 

MONIKA BHARGAVA, BHSC    

PAUL RICHARD SAUNDERS, PHD, ND 

In the United States and Canada, breast cancer is the most common cancer among women and the second leading cause of cancer death in women.^1,2 In 2014, it was estimated that in the year 2020, 27 640 Canadians (women and men) would be diagnosed with breast cancer and that 5155 Canadians would die from breast cancer.² Of these new cases, 99% would be women. Distressingly, it was estimated that about 1 in 8 Canadian women would develop breast cancer during their lifetime and that 1 in 33 patients would die from this condition.² This year, breast cancer is estimated to constitute 30% of all female cancers in the United States.³ In other words, more than one-quarter of all cancer diagnoses among American women will be breast cancer.  

The high incidence of breast cancer yearns for a solution to manage the treatment of breast cancer effectively, not only with conventional treatments, but also with naturopathic therapies in a collaborative care model. This type of all-rounded care can enhance the quality of treatment the patient receives and aims to improve the quality of life and overall survival outcome of breast cancer patients. The purpose of this review is to evaluate the most relevant research on the effectiveness of the adjunctive therapies, indole-3-carbinol and its derivative, diindolylmethane, to decrease breast cancer risk and enhance the effectiveness of tamoxifen for breast cancer outcomes, as compared to the conventional treatment of tamoxifen alone.   

Breast Cancer Risk Factors  

A major impediment in the ability to control cancer and treat it effectively has been the confusion surrounding the origin of the disease.⁴ Contradictions between theories have prevented the formation of a unified and efficacious strategy for long-term management and significant reduction in morbidity and mortality from cancer worldwide.⁴ Although the origin of cancer remains a mystery, risk factors for developing cancer have been identified by various academic researchers.  

Breast cancer involves the uncontrolled growth of epithelial cells in the breast.³ Typically, breast cancer is detected on exam as a hard, fixed, immobile mass, most commonly in the upper-outer quadrant of the breast.⁸ Certain breast cancers are associated with amplification and overexpression of genes for progesterone receptors, estrogen receptors, and HER2/neu (erbB2) receptors.⁹ These receptors are transmembrane glycoproteins and have tyrosine kinase activity that plays a crucial role in epithelial growth and differentiation.¹⁰ These receptors are important for both prognostic and therapeutic considerations in breast cancer.¹⁰  

Conventional Treatments  

Breast cancer is a heterogeneous disease characterized by diverse pathological types and diverse outcomes. Treatment options for breast cancer are individualized based on several factors. These include the patient’s age, health status, and menopausal status, as well as tumor stage, the subtype of the tumor, including its hormone receptor status (ie, estrogen receptor, progesterone receptor, or HER2), inherited breast cancer genes (eg, BRCA1 or BRCA2), other genomic markers, and the patient’s overall preferences.¹¹ The conventional treatment of breast cancer often includes surgery, radiation, chemotherapy, targeted therapy, immunotherapy, and/or hormone therapy.⁹  

Selective estrogen receptor modulators (SERMs) represent a type of conventional hormonal therapy used in breast cancers, specifically estrogen-receptor-positive cancers.^5,11 This treatment may be given as a neoadjuvant hormonal therapy to shrink tumors before surgery or as an adjuvant hormonal therapy after surgery to help lower the risk of cancer reoccurrence.^11,12 The primary treatment goals for hormonal drug therapies such as SERMs are the prevention and treatment of estrogen-receptor-positive pre-invasive and invasive breast cancers among women diagnosed with the disease or who are at high risk.¹²   

Tamoxifen 

For the past several decades, tamoxifen has been a gold standard endocrine treatment of estrogen-receptor-positive breast cancer, in all stages of the disease.^9,13 Although tamoxifen is considered an essential drug in the treatment of breast cancer by the World Health Organization, it was initially developed for contraceptive use.¹³ Ultimately, because of its anti-estrogen and anti-cancer properties, tamoxifen was reinvented as a therapy for breast cancer and brought to market in the United Kingdom.¹³ Tamoxifen has saved the lives of hundreds of thousands of women with breast cancer, and millions of others have benefited from around a 5% increase in disease-free survival and a 3% overall improvement in 10-year survival.^5,13 Women with stage I breast cancer are expected to take hormonal therapy for up to 5 years, and women with stage II or III cancer may be required to take tamoxifen for 10 years.¹¹  

Tamoxifen is a SERM that acts as an estrogen antagonist in breast tissue; hence, it is used as a preventive and treatment for estrogen-receptor-positive breast cancer.⁵ Because tamoxifen also acts as a partial estrogen agonist in bones, it is additionally used to help prevent osteoporosis in postmenopausal women.⁵ Other benefits of tamoxifen include decreased heart disease risk and slightly decreased risk of contralateral breast cancer.⁵ Tamoxifen side-effects include vaginal dryness, hot flashes, blood clots, increased risk of endometrial and liver cancers, poor concentration, depression, and visual impairment due to toxicity to the eyes.^1,5 Tamoxifen should not be used in patients with a history of thromboembolic events, macular degeneration, or use of oral contraceptives, SSRI antidepressants, grapefruit, St John’s wort, black cohosh, or red clover.⁵ Breast cancer cells can become resistant to tamoxifen by upregulating cytosolic and nuclear estrogen receptors that this SERM drug cannot access.⁵  

Tamoxifen was the first drug to be approved by the FDA for reducing breast cancer incidence in premenopausal and postmenopausal women at high risk.¹³ It continues to be used worldwide.¹³ Therefore, the value of tamoxifen for breast cancer outcomes is clear, and identifying adjunctive therapies that enhance the effectiveness of this drug is crucial. 

Nutritional Treatment: I3C & DIM 

Diet has proven to be a modifiable risk factor associated with breast cancer.¹⁴ Therefore, understanding the role of bioactive compounds of food origin in the form of nutritional supplements is important for strategizing cancer chemoprevention. 

 Indole-3-carbinol (I3C) is a phytochemical that occurs naturally in cruciferous vegetables.^1,14 Examples of crucifers, which are all members of the Brassicaceae family and contain I3C, include broccoli, bok choy, cabbage, cauliflower, collards, kale, Brussels sprouts, and kohlrabi.¹⁴ I3C is activated in the stomach and converted to its more heat-stable metabolite diindolylmethane (DIM).¹⁵   

Although research on I3C and DIM is mixed, I3C’s metabolite DIM has been shown in animal, in-vitro, and human studies to have protective effects for breast cancer, and may therefore be a valuable strategy to improve breast cancer outcomes.^14-16 I3C has been shown to stimulate both Phase 1 and Phase 2 detoxifying enzymes.¹⁵ I3C and DIM have been demonstrated to have direct anti-estrogenic activity through competitive inhibition of estrogen receptors, as well as by modulating activity of the cytochrome P450 enzymes CYP1A1, CYP1A2, and CYP1B1.¹⁷ Specifically, these metabolites are able to shunt the metabolism of estrogen away from the more carcinogenic 16-hydroxyestrogens and toward the more protective 2-hydroxyestrogens, as well as inhibit the production of procarcinogenic 4-hydroxyestrogens.^14,17,18 Women with higher ratios of 2-hydroxylation to 16-hydroxylation of estrogen have significantly lower risk of breast cancer compared to women with lower ratios.¹⁹ I3C also induces apoptosis in breast cancer cells through the NF pathways, induces a G1 cell cycle arrest in breast cancer cells, and is considered an antitumor agent. Besides its effects on breast cancer, I3C has antiviral properties and is used in the treatment of herpes simplex virus and human papillomavirus (HPV), the latter of which has been linked to cervical cancer.^17,18,20 In summary, I3C and DIM are important compounds for the prevention and treatment of breast cancer, as they are anti-estrogenic and have anti-cancer properties, including in breast cancer.  

Tamoxifen with I3C or DIM  

As discussed, both tamoxifen and the cruciferous compounds I3C and DIM have anti-estrogen and anti-cancer properties that make them useful therapies in breast cancer. For the purposes of this review, both I3C and its derivative, DIM, were assessed as adjunctive therapies with tamoxifen in terms of the effectiveness of the combined treatment vs each treatment alone, whether additional mechanisms might be involved in their anti-cancer effects, and to better understand their role in integrative cancer care.  

In a randomized, placebo-controlled trial of 12 months’ duration, patients with breast cancer who were prescribed tamoxifen were also orally supplemented with DIM (150 mg twice daily) or placebo.²¹ The biomarkers assessed during the study included the 2/16-hydroxyestrone ratio, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites. Compliance with the treatment was greater than 91%, with 51 patients in the placebo group and 47 patients in the treatment group administered DIM. In the DIM group, the 2/16-hydroxyestrone ratio increased compared to placebo (p <0.001). In the DIM group, serum SHBG also increased compared to placebo, an effect that has been shown to reduce breast cancer risk, at least partly by decreasing the amount of unbound estrogen in the body.²¹ Tamoxifen metabolites in women given DIM decreased (p<0.001), the clinical impact of which was unclear. No changes were seen in breast density.²¹ In summary, the addition of oral supplementation of DIM to tamoxifen in breast cancer patients provided additional favorable effects in lowering breast cancer risk, including estrogen metabolism and SHBG.²¹  

In another study, I3C and tamoxifen were used in combination in human breast cancer cells.²² Together, the compounds effectively inhibited the growth of the estrogen-dependent human MCF-7 breast cancer cells, and the effectiveness was greater in combination compared to either compound alone.²² This might have been due to the fact that I3C and tamoxifen work via different signal transduction pathways to suppress the growth of human breast cancer cells.²² If these results translate in vivo, they suggest an overall enhanced benefit of combined tamoxifen and I3C treatment for estrogen receptor-positive breast cancers.²²  

Summary 

Breast cancer is a significant public health concern, especially given its higher incidence compared to other cancer types among women.² Treating in the early stages of breast cancer produce the best outcomes for overall survival rates.² Therefore, it is imperative that women who are at high risk or have been diagnosed with early-stage breast cancer use prevention and treatment strategies that help slow the progression of the disease.^2-3 The conventional approach to preventing and treating estrogen-receptor-positive pre-invasive and invasive breast cancers commonly include the SERM drug, tamoxifen.¹¹ For an integrative approach to breast cancer that could enhance the effectiveness of tamoxifen, I3C and/or DIM should be considered as adjunctive agents, as they have anti-estrogenic and anti-cancer properties. Both I3C and its derivative, DIM, have demonstrated positive outcomes for breast cancer in breast cancer cell-line studies and clinical studies. Benefits of adding I3C or DIM to tamoxifen include shifting estrogen metabolism to the more protective 2-hydroxylation, increasing SHBG, favorably modifying signal transduction, and inducing cancer apoptosis.^14-16 Interestingly, over 2000 years ago, the physician Hippocrates prescribed cabbage leaf poultices to women with breast cancer; cabbage contains the bioactive compound I3C.¹¹ In summary, the inclusion of I3C and its metabolite DIM as a part of a primary integrative approach to enhance the effectiveness of tamoxifen in breast cancer patients is merited.   

References

1. Yang G, Nowsheen S, Aziz K, Georgakilas AG. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther. 2013;139(3):392-404.  

1. Canadian Cancer Society. Breast cancer statistics. Certified February 2014. Available at: https://cancer.ca/en/cancer-information/cancer-types/breast/statistics. Accessed November 14, 2020.  

1. American Cancer Society. Cancer Facts & Figures: 2021. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. Accessed October 24, 2021. 

1. Seyfried TN, Flores RE, Poff AM, D’Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35(3):515-527.  

1. McKinney N. Naturopathic Oncology: An Encyclopedic Guide for Patients and Physicians. Vancouver, BC: Liaison Press; 2010. 

1. Travis RC, Key TJ. Oestrogen exposure and breast cancer risk. Breast Cancer Res. 2003;5(5):239-247. 

1. Lange CA, Yee D. Progesterone and breast cancer. Womens Health (Lond). 2008;4(2):151-162. 

1. Chan S, Chen JH, Li S, et al. Evaluation of the association between quantitative mammographic density and breast cancer occurred in different quadrants. BMC Cancer. 2017;17(1):274. 

1. Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389(10074):1134-1150.   

1. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008;65(10):1566-1584. 

1. Parmar G. Textbook of Naturopathic Oncology: A Desktop Guide of Integrative Cancer Care. British Columbia, Canada: Medicatrix Holdings Ltd; 2020. 

1. National Cancer Institute. Breast Cancer Treatment (Adult) (PDQ®)–Patient Version. Last updated October 4, 2021.Available at: https://www.cancer.gov/types/breast/patient/breast-treatment-pdq. Accessed November 19, 2020.  

1. Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205-213.  

1. Thomson CA, Ho E, Strom MB. Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies. Nutr Rev. 2016;74(7):432-443.  

1. Maruthanila VL, Poornima J, Mirunalini S. Attenuation of Carcinogenesis and the Mechanism Underlying by the Influence of Indole-3-carbinol and Its Metabolite 3,3′-Diindolylmethane: A Therapeutic Marvel. Adv Pharmacol Sci. 2014;2014:832161. 

1. Firestone GL, Bjeldanes LF. Indole-3-carbinol and 3-3′-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr. 2003;133(7 Suppl):2448S-2455S.  

1. NDAssist. I3C SAP. Available at: https://www.nhpassist.com/products/nfh/i3c-sap. Accessed November 22, 2020.  

1. Bradlow HL, Sepkovic DW, Telang NT, Osborne MP. Multifunctional aspects of the action of indole-3-carbinol as an antitumor agent. Ann N Y Acad Sci. 1999;889:204-213.  

1. Sampson JN, Falk RT, Schairer C, et al. Association of Estrogen Metabolism with Breast Cancer Risk in Different Cohorts of Postmenopausal Women. Cancer Res. 2017;77(4):918-925. 

1. Marconett CN, Singhal AK, Sundar SN, Firestone GL. Indole-3-carbinol disrupts estrogen receptor-alpha dependent expression of insulin-like growth factor-1 receptor and insulin receptor substrate-1 and proliferation of human breast cancer cells. Mol Cell Endocrinol. 2012;363(1-2):74-84.  

1. Thomson CA, Chow HHS, Wertheim BC, et al. A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen. Breast Cancer Res Treat. 2017;165(1):97-107.  

1. Cover CM, Hsieh SJ, Cram EJ, et al. Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res. 1999;59(6):1244-1251. 

Monika Bhargava, BHSc was a 4th-year student at the Canadian College of Naturopathic Medicine at the time of this writing; she has since graduated. She is also a graduate of the TCM program at the Acupuncture and Integrative Medicine Academy. Monika’s research interests include the prevention and treatment of cancer using conventional and naturopathic medicine and adjunctive therapies. As a clinical intern at the Robert Schad Naturopathic Clinic and Queen West Community Heath Centre, she is excited to provide personalized treatments to optimize patient health.   

Paul Richard Saunders, PhD, ND is Adjunct Professor of Materia Medica at CCNM, and has a practice in Dundas, Ontario. He earned a PhD at Duke University, served at Clemson University, and tenured at Washington State University. Paul earned a DHANP and CCH. He was Ontario Naturopathic Doctor of the Year in 1994 and 2002. Paul established the Office of Natural Health Products, Health Canada. He is the president of NPLEX and has co-authored 3 books.  

breast cancer, Cancer, Cancer Cells, cancer risk, Cancer Treatment, cancers

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