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Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies.

Kwon Y - Food Sci Nutr (2014)

Bottom Line: However, the effect of isoflavones on breast cancer remains controversial.Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth.Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Engineering, Ewha Womans University Seoul, Korea.

ABSTRACT
Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors.

No MeSH data available.


Related in: MedlinePlus

The relative level of isoflavones and estrogen at the target site is an important factor that determines potential estrogen agonistic/antagonistic effect of soy isoflavones on the ER-positive tumor growth. Preclinical studies that use subcutaneous xenografts models might not properly reflect the relative levels of estrogen and isoflavones on human breast tumor where estrogen is provided by the surrounding stroma and isoflavones are less bioavailable. In this circumstance, dietary isoflavones might not have a significant estrogen agonist effect and, rather, could exert an estrogen antagonistic effect. Therefore, the relative levels of isoflavones and estrogen on human breast tumors should be considered more carefully in the preclinical study design and parameters that can estimate those levels should be included to determine the effect of isoflavones on the growth of human breast tumors in clinical/epidemiological studies.
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fig01: The relative level of isoflavones and estrogen at the target site is an important factor that determines potential estrogen agonistic/antagonistic effect of soy isoflavones on the ER-positive tumor growth. Preclinical studies that use subcutaneous xenografts models might not properly reflect the relative levels of estrogen and isoflavones on human breast tumor where estrogen is provided by the surrounding stroma and isoflavones are less bioavailable. In this circumstance, dietary isoflavones might not have a significant estrogen agonist effect and, rather, could exert an estrogen antagonistic effect. Therefore, the relative levels of isoflavones and estrogen on human breast tumors should be considered more carefully in the preclinical study design and parameters that can estimate those levels should be included to determine the effect of isoflavones on the growth of human breast tumors in clinical/epidemiological studies.

Mentions: Another question is whether the estrogen concentration in the breast tissue has been appropriately considered. It was suggested that the relative level of genistein and estrogen is an important factor that determines potential estrogen agonistic/antagonistic effect of genistein and the consequence of genistein intake on the growth of ER-positive breast tumor. Accordingly, many studies have tested whether genistein may act as an estrogen agonist and promote the growth of breast tumor under low local concentrations of estrogen (e.g., in postmenopausal women) (Hsieh et al. 1998; Allred et al. 2001a,b; Ju et al. 2001). In fact, genistein presented a greater growth stimulatory effect under the condition where estrogen was removed as much as possible (Martin et al. 1978). However, it should be also noted that estrogen levels in normal breast tissues are high and breast tumors have 10–50-fold higher estrogen level compared to the level in the blood, even in postmenopausal women (Yaghjyan and Colditz 2011). Moreover, it has been demonstrated that stromal cells surrounding breast tumors are the primary source of estrogen (Santen et al. 1997). In comparison, studies that presented the growth stimulatory effect of dietary genistein used a subcutaneous xenografts model (inoculating cancer cells into the flank of mice) in ovariectomized mice without providing extraneous estrogen. The flank of ovariectomized mice might present conditions of estrogen deprivation; therefore, the study design might not properly reflect the estrogen concentration in the breast tumor microenvironment. In the human breast tumor, the estrogen concentration might be higher whereas the isoflavone concentration might be lower (Maubach et al. 2004; Setchell et al. 2011) compared to the levels considered in the preclinical studies (Fig.1). In this circumstance, dietary genistein might not have a significant estrogen agonistic effect and, rather, could exert an estrogen antagonistic effect (Fig.1). It will be more informative to utilize culture systems or orthotopic animal models that consider the primary site of tumor formation as well as interactions of tumor cells with their physiological microenvironment (Killion et al. 1998; Cordero et al. 2010) to better reflect estrogen level at the target sites. It will be also important to include parameters that estimate the relative levels of estrogen and genistein concentrations in human breast tumors in clinical and epidemiological studies.


Effect of soy isoflavones on the growth of human breast tumors: findings from preclinical studies.

Kwon Y - Food Sci Nutr (2014)

The relative level of isoflavones and estrogen at the target site is an important factor that determines potential estrogen agonistic/antagonistic effect of soy isoflavones on the ER-positive tumor growth. Preclinical studies that use subcutaneous xenografts models might not properly reflect the relative levels of estrogen and isoflavones on human breast tumor where estrogen is provided by the surrounding stroma and isoflavones are less bioavailable. In this circumstance, dietary isoflavones might not have a significant estrogen agonist effect and, rather, could exert an estrogen antagonistic effect. Therefore, the relative levels of isoflavones and estrogen on human breast tumors should be considered more carefully in the preclinical study design and parameters that can estimate those levels should be included to determine the effect of isoflavones on the growth of human breast tumors in clinical/epidemiological studies.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256563&req=5

fig01: The relative level of isoflavones and estrogen at the target site is an important factor that determines potential estrogen agonistic/antagonistic effect of soy isoflavones on the ER-positive tumor growth. Preclinical studies that use subcutaneous xenografts models might not properly reflect the relative levels of estrogen and isoflavones on human breast tumor where estrogen is provided by the surrounding stroma and isoflavones are less bioavailable. In this circumstance, dietary isoflavones might not have a significant estrogen agonist effect and, rather, could exert an estrogen antagonistic effect. Therefore, the relative levels of isoflavones and estrogen on human breast tumors should be considered more carefully in the preclinical study design and parameters that can estimate those levels should be included to determine the effect of isoflavones on the growth of human breast tumors in clinical/epidemiological studies.
Mentions: Another question is whether the estrogen concentration in the breast tissue has been appropriately considered. It was suggested that the relative level of genistein and estrogen is an important factor that determines potential estrogen agonistic/antagonistic effect of genistein and the consequence of genistein intake on the growth of ER-positive breast tumor. Accordingly, many studies have tested whether genistein may act as an estrogen agonist and promote the growth of breast tumor under low local concentrations of estrogen (e.g., in postmenopausal women) (Hsieh et al. 1998; Allred et al. 2001a,b; Ju et al. 2001). In fact, genistein presented a greater growth stimulatory effect under the condition where estrogen was removed as much as possible (Martin et al. 1978). However, it should be also noted that estrogen levels in normal breast tissues are high and breast tumors have 10–50-fold higher estrogen level compared to the level in the blood, even in postmenopausal women (Yaghjyan and Colditz 2011). Moreover, it has been demonstrated that stromal cells surrounding breast tumors are the primary source of estrogen (Santen et al. 1997). In comparison, studies that presented the growth stimulatory effect of dietary genistein used a subcutaneous xenografts model (inoculating cancer cells into the flank of mice) in ovariectomized mice without providing extraneous estrogen. The flank of ovariectomized mice might present conditions of estrogen deprivation; therefore, the study design might not properly reflect the estrogen concentration in the breast tumor microenvironment. In the human breast tumor, the estrogen concentration might be higher whereas the isoflavone concentration might be lower (Maubach et al. 2004; Setchell et al. 2011) compared to the levels considered in the preclinical studies (Fig.1). In this circumstance, dietary genistein might not have a significant estrogen agonistic effect and, rather, could exert an estrogen antagonistic effect (Fig.1). It will be more informative to utilize culture systems or orthotopic animal models that consider the primary site of tumor formation as well as interactions of tumor cells with their physiological microenvironment (Killion et al. 1998; Cordero et al. 2010) to better reflect estrogen level at the target sites. It will be also important to include parameters that estimate the relative levels of estrogen and genistein concentrations in human breast tumors in clinical and epidemiological studies.

Bottom Line: However, the effect of isoflavones on breast cancer remains controversial.Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth.Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen.

View Article: PubMed Central - PubMed

Affiliation: Department of Food Science and Engineering, Ewha Womans University Seoul, Korea.

ABSTRACT
Breast cancer is the most common cancer among women worldwide, and many women with breast cancer live more than 5 years after their diagnosis. Breast cancer patients and survivors have a greater interest in taking soy foods and isoflavone supplements. However, the effect of isoflavones on breast cancer remains controversial. Thus, it is critical to determine if and when isoflavones are beneficial or detrimental to breast cancer patients. According to the available preclinical data, high concentrations of isoflavones inhibit the proliferation of breast cancer cells, regardless of their estrogen receptor (ER) status. In comparison, genistein, a major isoflavone, has stimulated tumor growth at low concentrations and mitigated tamoxifen efficacy in ER-positive breast cancer. Studies have indicated that the relative levels of genistein and estrogen at the target site are important to determine the genistein effect on the ER-positive tumor growth. However, studies using ovariectomized mice and subcutaneous xenograft models might not truly reflect estrogen concentrations in human breast tumors. Moreover, it may be an oversimplification that isoflavones stimulate hormone-dependent tumor growth due to their potential estrogenic effect since studies also suggest nonestrogenic anticancer effects of isoflavones and ER-independent anticancer activity of tamoxifen. Therefore, the concentrations of isoflavones and estrogen in human breast tumors should be considered better in future preclinical studies and the parameters that can estimate those levels in breast tumors are required in human clinical/epidemiological investigation. In addition, it will be important to identify the molecular mechanisms that either inhibit or promote the growth of breast cancer cells by soy isoflavones, and use those molecules to evaluate the relevance of the preclinical findings to the human disease and to predict the health effects of isoflavones in human breast tumors.

No MeSH data available.


Related in: MedlinePlus