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Women, Platelets & Cardiovascular Risk

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24 COVER STORY: THERAPEUTIC AND MOLECULAR EVI-DENCE FOR THE USE OF SOY AND RED CLOVER IN BREAST CANCER By Rochelle Fernandes, MSc., ND (Cand)

28 AN INTEGRATIVE APPROACH TO CANCER IN CANADA By Inna Levchuk

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34 WOMEN, PLATELETS & CARDIOVASCULAR RISK By Maria Shapoval (ND)

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COVER STORY

THERAPEUTIC AND MOLECULAR EVIDENCE FOR

THE USE OF SOY AND RED CLOVER IN

BREAST CANCER BY ROCHELLE FERNANDES, MSC., ND (CAND.)

Peer-reviewed by Jason Boxtart (ND), Dugald Seely (ND, MSc), Jill Shainhouse (ND, FABNO), Denise Cheung (ND, cand)

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FEBRUARY 2016 • IHRMAGAZINE.COM 25

B reast cancer is the most diagnosed cancer for women over 20, and is the second leading cause of cancer deaths in women, second to lung cancer (CCDP, 2005-2010). It is

thought that 24,000 Canadians will be diagnosed with breast cancer this year and 5,000 will die from it, as stated by the Canadian Breast Cancer Foundation (Coles 2013). Given these alarming statistics, along with the side effects of conventional treatment (i.e. fatigue, nausea, lymphedema, nerve damage and more), there has been an increas-ing interest in the use of natural supplements to prevent and treat cancer alone or alongside conventional options. This growing interest has included the controversial but promising use of phytoestrogens found in soy and red clover. The study of soy as a therapeutic ingre-dient has increased over the last decade. It has been researched for its use in alleviating menopausal hot �ashes, diminishing bone loss, reducing cholesterol levels and in cancer prevention (Messina 2010). There was a perceived notion that soy phytoestrogens were weak estrogen agonists/antagonists with molecular characteristics similar to synthetic endocrine disruptors that could theoretically disrupt hormones and promote cancer, however, this claim has not been con�rmed in human studies. In fact, soy may have a real role in the prevention and treatment of breast cancer.

Soy is a complete protein as it contains all the essential amino acids including histidine. It is known to be low in cysteine, which is required for infants, and therefore not recommended for use in infancy. Food sources of soybeans include soy milk and tofu. Fermented foods with soy are natto and fermented bean paste. The form and type of soy consumed should also be noted, as this has an impact on absorption after consumption. For instance, it is known that majority of the iso�avones in soy milk are glycosides, but they are converted to aglycones by fermentation (Takagi 2015). Iso�avone absorption is increased in fermented soy milk beverage (in which the iso�avones are largely converted to aglycones) in comparison to regular soy milk. Some consideration should be given to the fact that 93 per cent of soy is now a genetically modi�ed organism (GMO), and that it can cause allergic reactions in some, however, further studies are needed to assess the full effects of this (Kelly, 2015). Until this can be done, it is best to use non-GMO soy and to avoid usage if allergic.

It should be noted that people metabolize soy phytoestrogens dif-ferently. Soy contains iso�avones, such as genistein and daidzein. It also contains glycitein, an O-methylated iso�avone that makes up 5–10% of the total iso�avones in soy food (Song 1999). Equol is a gut bac-terial metabolite of the iso�avone daidzein, and has been associated with bene�cial health effects (Törmälä, 2007). Those with the intestinal capacity to convert daidzein to equol can change steroid metabolism

and estrogen bioavailability, and thus have an advantage using soy. Red clover is a plant that has been used in traditional medicine for

centuries. It has phytoestrogens coumestrol (CM) and formonone-tin (FM). It has been known for its use in asthma, cholesterol reduc-tion, hot �ashes, indigestion and cancer prevention. Recently, more research has been done on the use of red clover in female condi-tions, including menopause and cancer, alongside soy. The value of the use of phytoestrogens (found in soy and red clover) to combat cancer is now being assessed. For instance, one source suggests a therapeutic dose of 40-50mg of iso�avones (biochanin A, daidzein, formononetin and genistein) as daily dose for cancer prevention and additional health bene�ts, and this is derived from the traditional Japanese diet (Beck 2005).

MOLECULAR MECHANISMS OF SOY PHYTOESTROGENSSoy phytoestrogens are thought to be involved in breast cancer pre-vention through certain mechanisms of action. Genistein, for example, is believed to be involved in the modulation of different signaling path-ways associated with the growth of cancer cells through pleiotropic actions including inhibition of tyrosine kinases, DNA topoisomerase II, 5α-reductase, galectin-induced G2/M arrest, protein histidine kinase, and cyclin-dependent kinases (Varinska 2015). Another in vitro and in vivo study showed that genistein reduced MCF-7 cell proliferation and induced the inactivation of IGF-1R and p-Akt and downregulated the Bcl-2/Bax protein ratio (Chen 2014). Overall, these mechanisms have shown potential in breast cancer prevention.

MOLECULAR MECHANISMS OF RED CLOVER PHYTOESTROGENSMouse models and in vitro evidence have both shown interesting ways in which red clover iso�avones, such as formononetin (FM) can be preventative in breast cancer. Cells treated with FM have demonstrated reduced migration and invasion of MDA-MB-231 and 4T1 cells in a wound healing assay, chamber invasion assay, and an in vivo mouse metastasis model. In vitro, FM inhibited breast cancer cell migration and invasion by decreasing the expression of matrix metalloproteinase-2 (MMP-2), MMP-9 and increased the expres-sion of tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 (Zhou 2014). This �nding, while preliminary, suggests that FM may have anti-invasive properties for breast cancer, and that red clover deserves further evaluation in this context. Molecular evidence from Chen et al found that FM prevented the proliferation of MCF-7 cells and arrested the cell cycle in comparison to controls (Chen 2011).



COVER STORY

It should be noted that people metabolize soy phytoestrogens differently. Soy contains iso�avones, such as genistein and daidzein.

Levels of p-IGF-1R, p-Akt, cyclin D1 protein expression, and cyclin D1mRNA expression were also downregulated. FM also prevented tumor growth of human breast cancer cells in nude mouse xeno-grafts in the same study. Overall, these results show that FM halts the cell cycle at the G0/G1 phase by inactivating IGF1/IGF1R-PI3K/Akt pathways, which demonstrate its potential in preventing breast cancer carcinogenesis (Chen 2011).

HUMAN STUDIES OF THE PROTECTIVE EFFECT OF RED CLOVER AND SOYThere are many epidemiological studies that support the effects of soy and, a study for red clover, in either breast cancer prevention or treatment alongside other therapies. A recent systematic review suggested that soy food intake, similar to a traditional Japanese diet (2-3 servings daily, containing 25-50mg iso�avones) may be protective against breast cancer and its recurrence (Fritz 2013). One study, done on WHO-CARDIAC study populations, demonstrated that the lower mortalities of breast cancers were inversely related to the 24-h urinary iso�avone excretion (Yamori 2006). Another interesting, longitudinal, prospective study of breast cancer patients in China noted that soy food intake was safe and associated with a lower mortality and recurrence of breast cancer in patients (Shu 2009). A meta-analysis of breast cancer risk in Chinese women showed that soy was a relevant factor in reducing the risk of breast cancer development; signi�cant differences were also found between those who consumed soy foods, OR = 0.68 (95% CI 0.50-0.93) and those who ate a high-fat diet, OR = 1.15 (95% CI 1.01-1.30) (Wu 2015). One study proposed that soy should be used only in indicated patients and not in receptor positive females. Woo et al. found that high intake of soy iso�avones increased the risk of cancer recurrence in HER2-positive breast cancer patients (Woo, 2012), however, majority of the evidence proposes that soy is still protective.

Other convincing evidence comes from systematic reviews and meta-analyses, such as the one by Liu et al., which concluded that consumption of both soy and fruit was signi�cantly associated with a decreased risk of breast cancer, with summary ORs of 0.65 (95% CIs: 0.43-0.99; I2=88.9%, P<0.001; N=13) and 0.66 (95% CIs: 0.47-0.91; I2=76.7%, P<0.001; N=7), respectively (Liu 2014). A case control study support this �nding in Korean women; among soy foods, a high intake of cooked soybeans, including yellow and black soybeans, had an association with diminished risk of breast cancer (OR=0.67; 95% CI=0.45-0.91; P<0.02) (Do 2007). A case control German study showed that high and low consumption of soybeans, as well as of sun�ower and pumpkin seeds were associated with

signi�cantly reduced breast cancer risk compared to no consump-tion (OR = 0.83, 95% CI = 0.70-0.97; and OR = 0.66, 95% CI = 0.77-0.97, respectively) (Zaineddin 2012).

Research on red clover is limited, however, it still gives hope that could ease controversial claims that phytoestrogens, such as those found in red clover, may contribute to breast cancer or recurrence. One systematic review suggests that it may not promote breast cancer (Fritz 2013). Further studies for red clover are required to support the dietary use of phytoestrogens from this source and others.

CONCLUSIONOverall, molecular and human studies support the position that soy based phytoestrogens do not promote nor cause breast cancer ; rather, studies have shown that soy may decrease breast cancer risk, as well as protect against recurrence. Red clover is thought to act via similar mechanisms, however, requires further human study. For soy (preferably non GMO), supplementation has been thought to be more bene�cial in equol producers. It has also been found that breast cancer mortality was decreased in those with increased excretion of phytoestrogen metabolites (i.e. in the urine). There are some challenges in current research, such as a need to bridge the �ndings of observational studies to individual patient care (i.e. to address issues of intake and heterogeneity), however, a start would be to utilize doses with signi�cant results in current studies and move towards creating more structured, double-blind, placebo controlled trials whenever possible (Ballard-Barbish, 2009). A careful review of the evidence is required alongside a speci�c tailored regimen for each case and patient. It is important to consider the study popu-lation (Asian or other), estrogen receptor status and the presence or absence of menopause. Although interventional clinical trials are needed to conclusively assess the role of soy and red clover, the exist-ing research suggests that red clover and soy may have an important role to play in the prevention and treatment of breast cancer when used in the right context.

References Ballard-Barbish, R. a. (2009). Challenges in design and interpretation of observational research on health behaviors and cancer survival. JAMA, Dec 9;302(22):2483-4.Beck V1, Rohr U, Jungbauer A. Phytoestrogens derived from red clover: an alternative to estrogen replacement therapy? J Steroid Biochem Mol Biol. 2005 Apr;94(5):499-518. Epub 2005 Mar 23.CCDP, P. H. (2005-2010). Canadian Cancer Registry Database at Statistics Canada. Surveillance and Epidemiology Division CCDP.Chen J, Zeng J, Xin M, Huang W, Chen X. Formononetin induces cell cycle arrest


FEBRUARY 2016 • IHRMAGAZINE.COM 27

of human breast cancer cells via IGF1/PI3K/Akt pathways in vitro and in vivo. Horm Metab Res. 2011 Sep; 43(10):681-6. Epub 2011 Sep 19.Chen J1, Duan Y, Zhang X, Ye Y, Ge B, Chen J. Genistein induces apoptosis by the inactivation of the IGF-1R/p-Akt signaling pathway in MCF-7 human breast can-cer cells. Food Funct. 2015 Mar;6(3):995-1000. doi: 10.1039/c4fo01141d.Coles, Terri. 11 little known breast cancer facts. The Huf� ngton Post, 10/17/2014Do MH, Lee SS, Jung PJ, Lee MH. Intake of fruits, vegetables, and soy foods in relation to breast cancer risk in Korean women: a case-control study. Nutr Cancer. 2007; 57(1):20-7. Fritz H1, Seely D, Flower G, Skidmore B, Fernandes R, Vadeboncoeur S, Kennedy D, Cooley K, Wong R, Sagar S, Sabri E, Fergusson D. PLoS One. oy, red clover, and iso� avones and breast cancer: a systematic review.2013 Nov 28;8(11):e81968.Hejazi E, Nasrollahzadeh J, Fatemi R, Barzegar-Yar Mohamadi L, Saliminejad K, Amiri Z, Kimiagar M, Houshyari M, Tavakoli M, Idali F.Effects of Combined Soy Iso� avone Extract and Docetaxel Treatment on Murine 4T1 Breast Tumor Model. Avicenna J Med Biotechnol. 2015 Jan-Mar;7(1):16-21.Kelly, M. (2015, Aug 4). Top 7 genetically modi� ed crops. Retrieved from Huf� ngton Post: http://www.huf� ngtonpost.com/margie-kelly/genetically-modi-� ed-food_b_2039455.htmlLenka Varinska,1 Peter Gal,1,2,3,4 Gabriela Mojzisova,5 Ladislav Mirossay,1 and Jan Mojzis1,*: Soy and Breast Cancer: Focus on Angiogenesis. Int J Mol Sci. 2015 May; 16(5): 11728–11749Liu XO, Huang YB, Gao Y, Chen C, Yan Y, Dai HJ, Song FJ, Wang YG, Wang PS, Chen KX. Association between dietary factors and breast cancer risk among Chinese females: systematic review and meta-analysis. Asian Pac J Cancer Prev. 2014; 15(3):1291-8. Messina, Mark. A Brief Historical Overview of the Past Two Decades of Soy and Iso� avone Research J. Nutr. July 2010 vol. 140 no. 7 1350S-1354S

Messina MJ, Loprinzi CL .Soy for breast cancer survivors: a critical review of the literature.J Nutr. 2001 Nov; 131(11 Suppl):3095S-108S. Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W. Soy food intake and breast cancer survival. JAMA. 2009 Dec 9; 302(22):2437-43.Song TT, Hendrich S, Murphy PA (1999). "Estrogenic activity of glycitein, a soy iso� avone". Journal of Agricultural and Food Chemistry 47 (4): 1607–1610.Takagi A1, Kano M2, Kaga C3. Possibility of breast cancer prevention: use of soy iso� avones and fermented soy beverage produced using probiotics. Int J Mol Sci. 2015 May 13;16(5):10907-20Törmälä, R. A. (2007). Individual differences in equol production capability mod-ulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation. Climacteric, Dec;10(6):471-9.Woo, H. P. (2012). Differential in� uence of dietary soy intake on the risk of breast cancer recurrence related to HER2 status. Nutr Cancer, 64(2):198-205Wu YC1, Zheng D2, Sun JJ3, Zou ZK3, Ma ZL3. Meta-analysis of studies on breast cancer risk and diet in Chinese women. Int J Clin Exp Med. 2015 Jan 15;8(1):73-85. Yamori Y. Food factors for atherosclerosis prevention: Asian perspective derived from analyses of worldwide dietary biomarkers. Exp Clin Cardiol. 2006 Summer; 11(2):94-8.Zaineddin AK, Buck K, Vrieling A, Heinz J, Flesch-Janys D, Linseisen J, Chang-Claude J The association between dietary lignans, phytoestrogen-rich foods, and � ber intake and postmenopausal breast cancer risk: a German case-control study. Nutr Cancer. 2012; 64(5):652-65. Epub 2012 May 16.Zhou R, Xu L, Ye M, Liao M, Du H, Chen H.Formononetin inhibits migration and invasion of MDA-MB-231 and 4T1 breast cancer cells by suppressing MMP-2 and MMP-9 through PI3K/AKT signaling pathways. Horm Metab Res. 2014 Oct;46(11):753-60. doi: 10.1055/s-0034-1376977. Epub 2014 Jun 30.


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