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.  

For example, breast cancer risk increases in women of advanced age (>50 years) and who have a family history of breast cancer among first-degree relatives.⁵ Other risk factors include early onset of menarche, late onset of menopause, obesity, high-fat diet, high-glycemic diet, nulliparity, excess exposure to xenobiotics, exposure to ionizing radiation, depression, and alcohol consumption.⁵ Excess or chronic exposure to estrogen (eg, birth control pills >5 years or estrogen replacement therapy) and/or progesterone (and especially progestins) has also been associated with an increased risk of breast cancer.^5-7 It is clear that both modifiable and non-modifiable factors contribute to the risk of developing breast cancer. 

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.  

2. 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.  

3. 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. 

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

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

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

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

8. 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. 

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

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

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

12. 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.  

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

14. 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.  

15. 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. 

16. 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.  

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

18. 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.  

19. 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. 

20. 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.  

21. 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.  

22. 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.