Dietary Soy Isoflavones and Estrone Protect Ovariectomized ERαKO and Wild-Type Mice from Carcinogen-Induced Colon Cancer

Guo, Jiangtao; Li, Xiaosong; Browning, Jimmy D.; Rottinghaus, George E.; Lubahn, Dennis B.; Constantinou, Andreas I.; Bennink, Maurice R.; MacDonald, Ruth S.

doi:10.1093/jn/134.1.179

Cited by 88 publications

(62 citation statements)

References 22 publications

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“…Previous studies carried out in our laboratory and others have indicated that ERb, the primary ER within the colon, is the form of the receptor through which E 2 exerts its protective effects (Guo et al 2004, Weige et al 2009. Other groups have shown that ERbKO mice are more susceptible to inflammation-associated colon cancer than the WT mice (Saleiro et al 2012).…”

Section: Discussionmentioning

confidence: 85%

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A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Armstrong¹,

Billimek²,

Allred³

et al. 2013

Endocrine-Related Cancer

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Postmenopausal women on estrogen replacement therapy (ERT) have a reduced risk of developing colon cancer compared with postmenopausal women not on ERT, suggesting a role for estradiol (E 2 ) in protection against this disease. To determine whether E 2 protects against inflammation-associated colon cancer when administered following the initiation of colonic DNA damage, in this study, we implanted E 2 -containing pellets into mice after co-treatment with azoxymethane and two rounds of dextran sulfate sodium (DSS). Wild-type (WT) E 2 -treated mice had reduced numbers and average area of adenocarcinomas compared with the control mice. These effects were lost in estrogen receptor-b (Erb (Esr2)) knockout mice. Surprisingly, apoptosis was reduced and cell proliferation was increased in sections from tumors of the WT E 2 mice compared with the WT control mice. These findings are probably due, in part, to a reduction in ERb expression in colonic epithelial cells as the cells progressed from a non-malignant to a cancerous state as enhanced apoptosis was observed in normal colonocytes expressing higher levels of ERb. Furthermore, epithelial cells within the tumors had dramatically increased ERa mRNA and protein expression compared with the non-diseased mice. We conclude that while E 2 treatment resulted in an overall suppression of colonic adenocarcinoma formation, reduced ERb expression accompanied by enhanced ERa expression caused an altered colonocyte response to E 2 treatment compared with the earlier stages of colon cancer development. These data are the first examples of decreased ERb expression concurrent with increased ERa expression as a disease develops and highlight the importance of understanding the timing of E 2 exposure with regard to the prevention of inflammation-associated colon cancer.

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Section: Discussionmentioning

confidence: 85%

“…Additionally, the multiplicity of tumors induced by azoxymethane (AOM) was suppressed by orally administered estrone, a precursor to E 2 , in both estrogen receptor-a (Era (Esr1)) knockout (ERaKO) and wild-type (WT) mice (Guo et al 2004).…”

Section: Introductionmentioning

confidence: 99%

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Armstrong¹,

Billimek²,

Allred³

et al. 2013

Endocrine-Related Cancer

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show abstract

“…E 2 treatment in ovariectomized rats reduced dimethylhydrazine-induced tumor numbers in the colon by 71% (9). Orally administered estrone in ovariectomized wild-type (WT) and estrogen receptor (ER) α knockout mice inhibited formation of azoxymethane (AOM)-induced tumors (10). Data from this study are important because the fact that estrone suppressed tumor formation in both WT and ERα knockout mice shows that ERα is not the primary mediator for estrogenic protection in the colon.…”

Section: Introductionmentioning

confidence: 81%

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Weige

Allred

2009

Cancer Research

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Numerous clinical and animal studies show that hormone replacement therapy reduces the risk of colon tumor formation. However, the majority of experiments have shown that estradiol (E 2 ) does not inhibit the growth of malignantly transformed colon epithelia. As such, the presented studies focused on evaluating the effects of E 2 in noncancerous colonocytes. E 2 treatments (0-10 nmol/L) reduced cell growth and increased apoptotic activity in young adult mouse colonocytes (YAMC), a nonmalignant cell line, in a dose-responsive manner. These effects were lost in the YAMC-Ras cells, an isogenic cell line with a single malignant transformation. Cotreatment with an estrogen receptor (ER) antagonist inhibited the physiologic effects of E 2 in YAMC cells, suggesting that the response is ER mediated. To further study the effect of E 2 on colonic epithelia, we evaluated the development of preneoplastic lesions in ovariectomized wild-type (WT) and ERβ knockout (ERβKO) mice treated with either vehicle or E 2 . WT E 2 -treated animals exhibited significantly fewer aberrant crypt foci and increased apoptotic activity in colonic epithelia when compared with WT control mice or ERβKO animals receiving either treatment. For the first time, we showed that E 2 alters the growth of nontransformed colonocytes in vitro and that, through an ERβ-mediated mechanism, E 2 influences the physiology of noncancerous colonocytes, resulting in fewer preneoplastic lesions. Collectively, these data show that the protective actions of E 2 occur primarily during the initiation/promotion stages of disease development and identify the hormone as an important chemoprotective agent. [Cancer Res 2009;69(23):9118-24]

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“…Overall, the mice fed soy and treated with DSS had barrier protein expression similar to that of the casein-fed mice not treated with DSS, thereby suggesting a protective effect of soy protein independent of the probiotic. Soy components, such as lunasin, 78 fiber, 79 and isoflavones, 80 have been found to reduce inflammation and cancer in animal models. This and other studies clearly demonstrate that diet composition affects probiotic survival, that a wide variety of food components may influence colonic barrier function, and that future work needs to thoughtfully incorporate the interconnectedness of the colonic microbiome with diet and the disease process.…”

Section: ■ Probiotics Prebiotics and Colon Cancermentioning

confidence: 99%

Influence of Dietary Phytochemicals and Microbiota on Colon Cancer Risk

MacDonald

Wagner

2012

J. Agric. Food Chem.

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Colon cancer is the third most commonly diagnosed type of cancer in the United States. Lifestyle and dietary patterns influence colon cancer risk both positively and negatively. Among the dietary factors, several plantderived compounds have been found to afford colon cancer protection. These compounds potentially influence all aspects of colonic cellular regulation and develop complex interrelationships with the colonic microbiome. Increasing understanding of the role of microorganisms in determining the colonic environment has led to awareness of this important interrelationship among dietary factors and the microbial population. Plant-derived polyphenols are active mediators of cellular events, target key carcinogenic pathways, and modulate colonic microbial populations. In turn, the colonic microorganisms metabolize dietary compounds and mediate cellular events. In addition, the role of estrogen receptors in colon cancer and the importance of dietary components that mediate estrogen receptor-β are increasingly being discovered. Hence, dietary bioactive compounds and the intestinal microbiota create a complex milieu that directly affects the carcinogenic events of the colon. These relationships must be carefully characterized in future research to provide dietary recommendations that will reduce colon cancer risk. ABSTRACT: Colon cancer is the third most commonly diagnosed type of cancer in the United States. Lifestyle and dietary patterns influence colon cancer risk both positively and negatively. Among the dietary factors, several plant-derived compounds have been found to afford colon cancer protection. These compounds potentially influence all aspects of colonic cellular regulation and develop complex interrelationships with the colonic microbiome. Increasing understanding of the role of microorganisms in determining the colonic environment has led to awareness of this important interrelationship among dietary factors and the microbial population. Plant-derived polyphenols are active mediators of cellular events, target key carcinogenic pathways, and modulate colonic microbial populations. In turn, the colonic microorganisms metabolize dietary compounds and mediate cellular events. In addition, the role of estrogen receptors in colon cancer and the importance of dietary components that mediate estrogen receptor-β are increasingly being discovered. Hence, dietary bioactive compounds and the intestinal microbiota create a complex milieu that directly affects the carcinogenic events of the colon. These relationships must be carefully characterized in future research to provide dietary recommendations that will reduce colon cancer risk.

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Dietary Soy Isoflavones and Estrone Protect Ovariectomized ERαKO and Wild-Type Mice from Carcinogen-Induced Colon Cancer

Cited by 88 publications

References 22 publications

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

A novel shift in estrogen receptor expression occurs as estradiol suppresses inflammation-associated colon tumor formation

Estradiol Alters Cell Growth in Nonmalignant Colonocytes and Reduces the Formation of Preneoplastic Lesions in the Colon

Influence of Dietary Phytochemicals and Microbiota on Colon Cancer Risk

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