Abstract
Hormonal exposures are known to influence breast cancer risk among women with a BRCA1 mutation. Thus, dietary factors that increase the 2-hydroxyestrone (OHE):16α-OHE ratio, a biomarker inversely related to breast cancer development, may also influence cancer risk. We conducted a dietary intervention study to evaluate the ability of 300 mg/day of 3,3′-diindolylmethane (DIM) to increase the urinary 2:16α-OHE ratio in 20 women with a BRCA1 mutation. BRCA1 mutation carriers (n = 15) were assigned to receive 300 mg/day of Rx Balance BioREsponse DIM for 4–6 weeks (intervention group) and five BRCA1 mutation carriers did not take DIM (control group). The urinary 2:16α-OHE ratio was assessed at baseline and after 4–6 weeks by immunoassay. There was no significant effect of DIM on the 2:16α-OHE ratio (2.4 at baseline vs. 3.0 after the intervention, P = 0.35). A short dietary intervention with DIM did not significantly increase the 2:16α-OHE ratio in female BRCA1 mutation carriers. Larger studies investigating the effect of dietary or lifestyle interventions on circulating hormone levels in these high-risk women are warranted.
References
Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE (1994) Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 343(8899):692–695
Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130
Narod SA (2010) BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 7(12):702–707
Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L et al (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20(9):2310–2318
Rebbeck TR, Levin AM, Eisen A, Snyder C, Watson P, Cannon-Albright L et al (1999) Breast cancer risk after bilateral prophylactic oophorectomy in BRCA1 mutation carriers. J Natl Cancer Inst 91(17):1475–1479
Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL et al (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356(9245):1876–1881
Kotsopoulos J, Lubinski J, Moller P, Lynch HT, Singer CF, Eng C et al (2014) Timing of oral contraceptive use and the risk of breast cancer in BRCA1 mutation carriers. Breast Cancer Res Treat 143(3):579–586
Widschwendter M, Rosenthal AN, Philpott S, Rizzuto I, Fraser L, Hayward J et al (2013) The sex hormone system in carriers of BRCA1/2 mutations: a case–control study. Lancet Oncol 14(12):1226–1232
Obi N, Vrieling A, Heinz J, Chang-Claude J (2011) Estrogen metabolite ratio: is the 2-hydroxyestrone to 16α-hydroxyestrone ratio predictive for breast cancer? Int J Womens Health 3:37–51
Im A, Vogel VG, Ahrendt G, Lloyd S, Ragin C, Garte S et al (2009) Urinary estrogen metabolites in women at high risk for breast cancer. Carcinogenesis 30(9):1532–1535
Adlercreutz H, Fotsis T, Hockerstedt K, Hamalainen E, Bannwart C, Bloigu S et al (1989) Diet and urinary estrogen profile in premenopausal omnivorous and vegetarian women and in premenopausal women with breast cancer. J Steroid Biochem 34(1–6):527–530
Kabat GC, Chang CJ, Sparano JA, Sepkovie DW, Hu XP, Khalil A et al (1997) Urinary estrogen metabolites and breast cancer: a case–control study. Cancer Epidemiol Biomark Prev 6(7):505–509
Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill A, Ross RK et al (1999) Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 91(12):1067–1072
Meilahn EN, De Stavola B, Allen DS, Fentiman I, Bradlow HL, Sepkovic DW et al (1998) Do urinary oestrogen metabolites predict breast cancer? Guernsey III cohort follow-up. Br J Cancer 78(9):1250–1255
Muti P, Bradlow HL, Micheli A, Krogh V, Freudenheim JL, Schunemann HJ et al (2000) Estrogen metabolism and risk of breast cancer: a prospective study of the 2: 16alpha-hydroxyestrone ratio in premenopausal and postmenopausal women. Epidemiology 11(6):635–640
Ho GH, Luo XW, Ji CY, Foo SC, Ng EH (1998) Urinary 2/16 alpha-hydroxyestrone ratio: correlation with serum insulin-like growth factor binding protein-3 and a potential biomarker of breast cancer risk. Ann Acad Med Singap 27(2):294–299
Zheng W, Dunning L, Jin F, Holtzman J (1998) Correspondence re: G. C. Kabat et al., Urinary estrogen metabolites and breast cancer: a case–control study. Cancer Epidemiol Biomark Prev 6:505–509
Zheng W, Dunning L, Jin F, Holtzman J (1998) Correspondence re: G. C. Kabat et al., Urinary estrogen metabolites and breast cancer: a case–control study. Cancer Epidemiol Biomark Prev 7(1):85–86
Fowke JH, Qi D, Bradlow HL, Shu XO, Gao YT, Cheng JR et al (2003) Urinary estrogen metabolites and breast cancer: differential pattern of risk found with pre- versus post-treatment collection. Steroids 68(1):65–72
Kabat GC, O’Leary ES, Gammon MD, Sepkovic DW, Teitelbaum SL, Britton JA et al (2006) Estrogen metabolism and breast cancer. Epidemiology 17(1):80–88
Wellejus A, Olsen A, Tjonneland A, Thomsen BL, Overvad K, Loft S (2005) Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study. Cancer Epidemiol Biomark Prev 14(9):2137–2142
Cauley JA, Zmuda JM, Danielson ME, Ljung BM, Bauer DC, Cummings SR et al (2003) Estrogen metabolites and the risk of breast cancer in older women. Epidemiology 14(6):740–744
McTiernan A, Wu L, Chen C, Chlebowski R, Mossavar-Rahmani Y, Modugno F et al (2006) Relation of BMI and physical activity to sex hormones in postmenopausal women. Obesity 14(9):1662–1677
Eliassen AH, Missmer SA, Tworoger SS, Hankinson SE (2008) Circulating 2-hydroxy- and 16alpha-hydroxy estrone levels and risk of breast cancer among postmenopausal women. Cancer Epidemiol Biomark Prev 17(8):2029–2035
Ursin G, London S, Yang D, Tseng CC, Pike MC, Bernstein L et al (2002) Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and family history of breast cancer in premenopausal women. Breast Cancer Res Treat 72(2):139–143
Obi N, Vrieling A, Heinz J, Chang-Claude J (2011) Estrogen metabolite ratio: is the 2-hydroxyestrone to 16alpha-hydroxyestrone ratio predictive for breast cancer? Int J Womens Health 3:37–51
Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF (2004) Pilot study: effect of 3,3′-diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutr Cancer 50(2):161–167
Miller PE, Snyder DC (2012) Phytochemicals and cancer risk: a review of the epidemiological evidence. Nutr Clin Pract 27(5):599–612
Fan S, Meng Q, Auborn K, Carter T, Rosen EM (2006) BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells. Br J Cancer 94(3):407–426
Nkondjock A, Ghadirian P, Kotsopoulos J, Lubinski J, Lynch H, Kim-Sing C et al (2006) Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer 118(1):103–107
Kotsopoulos J, Zhang S, Akbari M, Salmena L, Llacuachaqui M, Zeligs M et al (2014) BRCA1 mRNA levels following a 4-6-week intervention with oral 3,3′-diindolylmethane. Br J Cancer 111(7):1269–1274
Bradlow HL, Sepkovic DW, Klug T, Osborne MP (1998) Application of an improved ELISA assay to the analysis of urinary estrogen metabolites. Steroids 63(7–8):406–413
Reed GA, Sunega JM, Sullivan DK, Gray JC, Mayo MS, Crowell JA et al (2008) Single-dose pharmacokinetics and tolerability of absorption-enhanced 3,3′-diindolylmethane in healthy subjects. Cancer Epidemiol Biomark Prev 17(10):2619–2624
Heath EI, Heilbrun LK, Li J, Vaishampayan U, Harper F, Pemberton P et al (2010) A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3′-diindolylmethane) in castrate-resistant, non-metastatic prostate cancer. Am J Transl Res 2(4):402–411
Rajoria S, Suriano R, Parmar PS, Wilson YL, Megwalu U, Moscatello A et al (2011) 3,3′-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: a pilot study. Thyroid 21(3):299–304
Fan S, Meng Q, Saha T, Sarkar FH, Rosen EM (2009) Low concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protect against oxidative stress in a BRCA1-dependent manner. Cancer Res 69(15):6083–6091
Berstein LM, Koskela A, Boyarkina MP, Adlercreutz H (2010) Excretion of estrogens, catecholestrogens and phytoestrogens in carriers of BRCA1 gene mutations: effects of metformin. Neoplasma 57(4):333–338
Chand AL, Simpson ER, Clyne CD, kConFab (2009) Aromatase expression is increased in BRCA1 mutation carriers. BMC Cancer 9:148
Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL et al (2000) Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case–control study. Hereditary Breast Cancer Clinical Study Group. Lancet 356(9245):1876–1881
Narod SA (2006) Modifiers of risk of hereditary breast cancer. Oncogene 25(43):5832–5836
Narod SA (2002) Modifiers of risk of hereditary breast and ovarian cancer. Nat Rev Cancer 2(2):113–123
Landi MT, Sinha R, Lang NP, Kadlubar FF (1999) Human cytochrome P4501A2. IARC Sci Publ 148:173–195
Abdull Razis AF, Bagatta M, De Nicola GR, Iori R, Ioannides C (2010) Intact glucosinolates modulate hepatic cytochrome P450 and phase II conjugation activities and may contribute directly to the chemopreventive activity of cruciferous vegetables. Toxicology 277(1–3):74–85
Huang Z, Zuo L, Zhang Z, Liu J, Chen J, Dong L et al (2011) 3,3′-Diindolylmethane decreases VCAM-1 expression and alleviates experimental colitis via a BRCA1-dependent antioxidant pathway. Free Radic Biol Med 50(2):228–236
Aggarwal BB, Ichikawa H (2005) Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 4(9):1201–1215
Bazzan AJ, Zabrecky GP, Newberg AB (2013) Multi-nutrient supplement improves hormone ratio associated with cancer risk. J Transl Med 11:252
Yamazaki H, Shaw PM, Guengerich FP, Shimada T (1998) Roles of cytochromes P450 1A2 and 3A4 in the oxidation of estradiol and estrone in human liver microsomes. Chem Res Toxicol 11(6):659–665
Acknowledgments
We would also like to acknowledge the study coordinators Chantelle Vernon and Mitra Mohammadi who helped with the data collection and data entry. Joanne Kotsopoulos is the recipient of a Cancer Care Ontario Research Chair in Population Studies and a Canadian Cancer Society Career Development Award in Prevention. Steven Narod is the recipient of a Canada Research Chair tier I. This study was supported by a Grant from the Art for Cancer Foundation. We would also like to thank Dr. Michael Zeligs (Bioresponse) for providing the DIM.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nikitina, D., Llacuachaqui, M., Sepkovic, D. et al. The effect of oral 3,3′-diindolylmethane supplementation on the 2:16α-OHE ratio in BRCA1 mutation carriers. Familial Cancer 14, 281–286 (2015). https://doi.org/10.1007/s10689-015-9783-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-015-9783-2