Soy and Breast Cancer | Portland, OR | Lee Dennis, ND

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Lee Dennis, ND

Naturopathic Physician

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Portland, OR 97233


Soy and Breast Cancer

by Lee Dennis, ND

Posted: September 16, 2013

Soy contains substances known as isoflavones that are known to have estrogenic effects in the body. Because of this, there has been much debate over whether or not soy foods are beneficial or detrimental in regards to breast cancer. In studying the effects of soy on breast cancer one must consider many facets including the level of dietary intake, the levels of isoflavones reached in breast tissue, the mechanism of action on breast tissue, the effect on women of varying hormonal status (premenopausal versus postmenopausal) and the effects after diagnosis of breast cancer. Additionally, does the effect on breast cancer vary depending on what type of cancer it is? For example, does soy have a different effect on estrogen receptor positive breast cancer in comparison to estrogen receptor negative cancer? These are all important aspects to consider when deciding if the usage of soy is beneficial or detrimental.

Isoflavones are theorized to assert their actions in a number of ways in breast tissue - one of which is their interaction with estrogen receptors (ER) found there. There are two types of estrogen receptors (ER) found in breast tissue - ERa and ERb. ER related carcinogenesis has mainly been linked to stimulation of ERa, with ERb stimulation decreasing the activity of ERa (Bolca et al., 2010, p. 982). Isoflavones are thought to interact more strongly with ERb (Bolca et al., 2010, p. 982). The level of interaction, however, depends on the type of isoflavone or isoflavone metabolite involved. For example, glucuronidation of the isoflavones genistein and daidzein decreases their estrogen activity (Bolca et al., 2010, p. 983). This means that isoflavone effects on breast tissue are largely dependent on the type of metabolite involved and the concentration level achieved. Another possible way that isoflavones can exert their effects is by inhibiting endogenous estrogen production. Experiments have shown that isoflavones inhibit aromatase and 17b-hydroxysteroid dehydrogenases which are peripheral converters of androgens and estrone to estradiol (Kang, Zhang, Wang, Huang, & Jin, 2010, p. 1861). Additionally, isoflavones have been found to alter methylation of key genes involved in the development of breast cancer (RARb2 and CCND) which could thereby alter gene transcription. (Qin et al, 2007, p. 242).

As mentioned previously, the type of isoflavone metabolite found in breast tissue determines its activity. Since the type of metabolite involved matters, one must be sure that the subjects of study metabolize isoflavones similarly. A study by Setchell et al (2011) discovered that the metabolism of isoflavones varies between rodents and humans. Since studies on rats and mice are often used to infer effects and design studies on humans, one must be careful in this particular case. The study found that phase II metabolism in some rodents varies significantly from human metabolism leading to a higher level of unconjugated, and therefore more active, isoflavones in plasma. (Setchell et al, 2011, p 1292) One can therefore conclude that the effects from isoflavones seen in rodents may not reflect what is found in humans.

Since isoflavones are thought to affect breast tissue by various mechanisms, it is important to determine if isoflavones can reach concentration levels in breast tissue to a level that would produce noticeable effects. To answer this question, a study by Bolca et al attempted to determine what concentration level various soy isoflavones reached in breast tissue after dietary consumption of soy foods. They used soy milk or a soy supplement (containing genistein and daidzein) versus a control group with no soy intake (Bolca et al., 2010, p. 977). Patients were given either of the above three times a day for a period of five days, at which point blood and breast tissue samples were collected and analyzed. They found that total isoflavone concentrations in breast tissue reached levels approximately 21-40 times that of estradiol (Bolca et al., 2010, p. 982). With these findings, Bolca et al. (2010) concluded that isoflavone levels in breast tissue can reach levels that may indeed have potential health implications.

The findings by Bolca et al. give more credence to the many epidemiological studies that correlate increased dietary levels of soy foods with an overall decreased risk for breast cancer. A meta-analysis by Qin et al. (2006) looked at a number of studies performed in multiple countries including China, Japan and the United States. These consisted of 14 case-control studies and 7 cohort studies. The meta-analysis found that high intake of soy foods was associated with a decreased risk of breast cancer (Qin et al., 2006, p. 434). The effect was stronger for premenopausal women as compared to postmenopausal women (Qin et al., 2006, 433). The study also found that intake of soy early in life had a long-term protective effect against breast cancer (Qin et al., 2006, p. 433).

From this study, there appears to be an overall protective effect from soy on developing breast cancer, but what about recurrence of breast cancer? A study by Nechuta et al. (2012) looked at soy intake and the risk of breast cancer recurrence and mortality from recurrence. This study looked at 9,514 breast cancer survivors from 2 US cohorts and 1 Chinese cohort. Dietary intake of soy foods was assessed via validated food frequency questionnaires. Nechuta et al. found that higher intakes of soy foods decreased the risk of recurrence of breast cancer (Nechuta et al, 2012, p. 127). Women with the highest intakes had a 36% reduced risk of recurrence compared to those with the lowest intakes of soy foods (Nechuta et al, 2012, p. 127). In this study, the trend was stronger for postmenopausal women compared to premenopausal women (Nechuta et al., 2012, p. 130). This study also found that patients with the highest soy intake had a 29% decreased risk of mortality from breast cancer (Nechuta et al, 2012, p. 127). The affects on ER positive breast cancers were a bit different as will be discussed below.

An in vitro study performed by Mai, Blackburn & Zhu (2007) showed that soy may also have a protective effect with ER positive breast cancers - at least in combination with tamoxifen. The combined therapy was found to decrease the expression of ERa and HER2 (Mai et al, 2007, p. 7). Furthermore, the combined therapy down regulated the expression of survivin (a protein that inhibits apoptosis), thereby effectively promoting apoptosis of tumor cells (Mai et al, 2007, p. 6).

These findings were confirmed in the prospective study by Nechuta et al. Patients on tamoxifen therapy with the highest intake of isoflavones had a statistically significant decreased risk of breast cancer recurrence (Nechuta et al, 2012, p. 128). Similar results were found with anastrozole - an aromatase inhibitor. Patients with the highest intakes of isoflavones with concurrent anastrozole therapy had lower rates of breast cancer recurrence (Kang et al., 2010, p. 1860). This decreased rate of recurrence may be due to synergistic inhibition of aromatase enzymes (Kang et al, 2010, p. 1861).

The effects of isoflavones on ER positive breast cancer without concurrent use of tamoxifen or anastrozole are less clear. Nechuta et al. (2012) found no statistically significant association between soy intake and recurrence of ER positive breast cancer without tamoxifen use.

Since much of the data showing the protective effects of soy are based on epidemiological studies, there is always the possibility of other variables influencing the data. In the study performed by Nechuta et al., they found that a higher intake of soy was associated with several other factors including regular exercise, a higher intake of cruciferous vegetables, lower BMI and no tobacco use. Many of these factors are known to be associated with lowering cancer risk and improving cancer outcomes. While these variables are generally statistically accounted for, one cannot completely rule out their possible influence.

The data reviewed in this paper supports an overall decreased risk of breast cancer associated with soy intake. Therefore, using soy products as part of a dietary and lifestyle program to help decrease risk of mortality from breast cancer and to prevent breast cancer recurrence is also supported. Of particular interest is the concurrent use of the popular tamoxifen drug in conjunction with soy foods to enhance the effectiveness of tamoxifen and also decrease the occurrence of tamoxifen resistance by breast tumors. The usage of soy in ER positive breast cancers without concurrent endocrine therapy is still questionable. Further research may be needed in this area.

Sources

Bolca, S., Urpi-Sarda, M., Blondeel, P., Roche, N., Vanhaecke, L., Possemiers, S., ... Depypere, H. (2010). Disposition of soy isoflavones in normal human breast tissue. American Journal of Clinical Nutrition, 91, 976-84.

Kang, X., Zhang, Q., Wang, S., Huang, X., & Jin, S. (2010). Effect of soy isoflavones on breast cancer recurrence and death for patients receiving adjuvant endocrine therapy. Canadian Medical Association Journal, 182(17), 1857-1862.

Mai, Z., Blackburn, G. L., & Zhou, J.-R. (2007). Genistein sensitizes inhibitory effect of tamoxifen on the growth of estrogen receptor-positive and HER2-overexpressing human breast cancer cells. Molecular Carcinogenesis, 46(7), 534-42.

Nechuta, S. J., Caan, B. J., Chen, W. Y., Lu, W., Chen, Z., Kwan, M. L., ... Shu, X. O. (2012). Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women. American Journal of Clinical Nutrition, 96, 123-32.

Qin, L.-Q., Xu, J.-Y., Wang, P.-Y., & Hoshi, K. (2006). Soyfood intake in the prevention of breast cancer risk in women: a meta-analysis of observational epidemiological studies. Journal of Nutritional Science and Vitaminology, 52, 428-436.

Setchell, K. D., Brown, N. M., Zhao, X., Lindley, S. L., Heubi, J. E., King, E. C., & Messina, M. J. (2011). Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk. American Journal of Clinical Nutrition, 94, 1284-94.





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