Beneficial Estrogen Metabolism in Breast Cancer

The Benefits of Diindolylmethane 
(DIM)

Diindolylmethane is formed in the body through digestion of plant substances contained in “cruciferous” vegetables such as cabbage, Brussels sprouts, cauliflower, and broccoli. Scientists think these vegetables may help to protect the body against cancer because they contain diindolylmethane and a related chemical called indole-3-carbinol. (1)

AFFECTS IN THE BODY

DIM has the biological properties listed in the chart below. Because of its various potential anticancer properties, including estrogen metabolism, the National Cancer Institute of the United States has begun clinical trials of DIM as a therapeutic for numerous forms of cancer including breast cancer. (2) 

Biological activities of 3,3'-diindolylmethane

HEALTHY ESTROGEN METABOLISM
The standard explanation for the association of cumulative, excessive estrogen exposure and breast cancer risk is that estrogen and perhaps progesterone affect the rate of cell division; and thus manifest their effect on the risk of breast cancer by causing proliferation of breast epithelial cells. Proliferating cells are susceptible to genetic errors during DNA replication which, if uncorrected, can ultimately lead  to a malignant phenotype. (3) Oxidative metabolites of estrogens have been implicated in the development of breast cancer, thus addressing estrogen metabolism can be a method of prevention.

According to National Cancer Institute: “Diindolylmethane promotes beneficial estrogen metabolism in both sexes by reducing the levels of 16-hydroxy estrogen metabolites (“bad estrogens”) and increasing the formation of 2-hydroxy estrogen metabolites (“good estrogens”), resulting in increased antioxidant activity.”

SUPPORTING EVIDENCE
DIM supplementation has been shown to alter estrogen urinary metabolites in women. In a prospective placebo-controlled pilot study 19 post-menopausal women with a history of early stage breast cancer were randomized to receive 108mg DIM or placebo for thirty days. Urinary metabolite analysis was conducted for 2-hydroxyestrone (2OHE-1), 16-alpha hydroxyestrone (16alpha=OHE-1), DIM, estrone (E1), estradiol (E2), estriol (E3), 6beta-hydroxycortisol (6betaOHC) and cortisol. The treatment group demonstrated significant increases in levels of 2-OHE1 (P=0.020), DIM (P=0.045), and cortisol (P=0.039) and a non-significant increase in the 2-OHE1/16alpha-OHE1 ratio from 1.46 to 2.14 (P=0.059). The results of this study demonstrate that DIM supplementation increases 2-hydroxylation of urinary estrogen metabolites. But whether this translates to reduced cancer risk has not been confirmed. (4)

Evidence continues to build supporting the use of DIM and its potential as a therapeutic agent in breast cancer prevention and possible treatment. The standard recommended dosage of bioavailable DIM for women is 100-200 mg of DIM daily. Men typically need a higher dose than women, such as 200-400 mg per day.

A review of active clinical trials involving DIM:
http://clinicaltrials.gov/ct/search?term=diindolylmethane

Additional reading on Healthy Estrogen Metabolism and DIM:
http://www.dimfaq.com/

References:

1. http://www.webmd.com/vitamins-supplements/ingredientmono-1049-DIINDOLYLMETHANE.aspxactiveIngredientId=1049&activeIngredientName=DIINDOLYLMETHANE
2. http://en.wikipedia.org/wiki/3%2C3%27-Diindolylmethane
3. Afr J Reprod Health. 2006 Apr;10(1):13-25.
4. Nutr Cancer. 2004;50(2):161-7.
Image courtesy of http://bonnieplants.com/wp-content/uploads/2011/10/brussels-sprouts-growing-lo.jpg

FLAXSEED USE IN BREAST CANCER

Current Research

Flaxseed, also known as linseed, is prominently known for its high content of omega-3 fatty acids, fiber and lignans. It is mainly because of the lignans however, that the seed has gained popularity and become a food of interest in breast cancer research.

According to a study published in 2011 in The Journal of Nutrition the phytoestrogen lignans are naturally occurring compounds with structural similarity to endogenous estrogens. Lignans are widely available in whole grains, seeds, nuts, legumes, fruit, and vegetables, with the highest concentration in flaxseed and bakery products containing flaxseed.

In human and experimental studies, high lignan intakes (from flaxseed) affect endocrine and growth factor pathways through a number of mechanisms, including modification of steroid hormone metabolism, modification of insulin-like growth factor and epidermal growth factor, and inhibition of aromatase and 17β-hydroxysteroid dehydrogenase. Lignans inhibit cell proliferation in both ER+ and ER− cell lines, reduce tumor growth and metastasis in a number of animal models, and work synergistically with Tamoxifen to reduce tumor growth. 

Several, but not all, epidemiologic studies report reduced risks of breast cancer associated with higher exposure to dietary lignans, expressed as either dietary intakes or as plasma, serum, or urinary lignan concentrations. The protective effect of lignans may also be stronger in specific subgroups of women with breast cancer; lower risks have been reported to be limited to premenopausal women, women with specific CYP17 genotypes, and recently for ER− breast cancer (1).

Several studies have found that higher lignan intakes were associated with lower risks of breast cancer with more favorable prognostic characteristics, lower tumor biomarkers and inhibition of the growth and metastasis of human breast cancer (2). 

All this said, Ruth Patterson, PhD who wrote an article entitled: Flaxseed and Breast Cancer: What Should We Tell Our Patients? in the Journal of Clinical Oncology states, "the prudent clinician should be wary of recommending high doses of any dietary compound solely on the basis of laboratory and observational epidemiologic studies". She based this opinion on the fact that in humans, lignans are metabolized by the gut microflora into enterolignans; enterolactone is the main metabolite. Therefore, enterolactone concentrations in serum, plasma, and urine have been used as biomarkers of dietary lignans. Studies indicate that women with higher levels of serum enterolactone have approximate 40% reduced risk of overall mortality and distant disease. 

However positive this seems, there happen to be several variables that must be considered when using enterolactones as a secure indicator Patterson states: "Serum enterolactone concentrations are an imperfect measure of dietary intake because they reflect (in unknown proportions) dietary intake of lignans, other dietary and environmental exposures, and host characteristics" (3). Thus the take home message is baseline levels of enterolactones obtained from our daily diet may be supportive for breast cancer risk reduction but supplementing with higher quantities may or may not achieve this outcome.

Continued research is warranted to support supplemental flaxseed intake for breast cancer prevention and support. I recommend the use of flaxseed to be a part of a balanced diet using 1-2 tablespoon daily and only 1 tablespoon daily as an upper limit in ER+ patients.

Additional reading from leading cancer institutes:

Dana-Farber Cancer Institute 

http://www.dana-farber.org/Health-Library/Phytoestrogen-s-Role-in-Estrogen-Positive-Breast-Cancer-Patients.aspx

Memorial Sloan-Kettering Cancer Center

http://www.mskcc.org/cancer-care/herb/flaxseed

American Institute for Cancer Research

http://www.aicr.org/assets/docs/pdf/education/FlaxseedBreastCancer.pdf

References

1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3237232/

2. http://www.mskcc.org/cancer-care/herb/flaxseed

3. http://jco.ascopubs.org/content/29/28/3723

Image courtesy of: http://www.wikihow.com/Prepare-Flax-Seeds