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© 2007 The American Society for Nutrition J. Nutr. 137:211S-215S, January 2007

Supplement: International Research Conference on Food, Nutrition, and Cancer

Gender-Specific Modulation of Markers for Premalignancy by Nutritional Soy and Calcium in the Mouse Colon1–3,

Giovanna Bises4, Erika Bajna4, Theresa Manhardt4, Waltraud Gerdenitsch5, Enikoe Kallay4 and Heide S. Cross4,*

4 Institute of Pathophysiology and 5 Center for Animal Care, Medical University of Vienna, A-1090 Vienna, Austria

* To whom correspondence should be addressed. E-mail: heide.cross{at}meduniwien.ac.at.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Sporadic colorectal cancer develops as a multistep process during decades of latency. Multiple factors, in particular nutrition, influence progression. Both nutritional calcium and soy are known to reduce sporadic cancer incidence. Soy contains high levels of phytoestrogens. Among them genistein is recognized as an antioxidant and cell-cycle inhibitor. However, timing and length of consumption of genistein as well as gender- and colon site–specific activity may result in beneficial or detrimental effects. We therefore evaluated the effect in mice of a basic AIN76A diet containing 20% soy as main protein source fed for 1 or 2 generations. In another set of animals, normal calcium levels (0.5%) were replaced by low calcium (0.04%) with or without supplementation of genistein (0.04%). Expression of the vitamin D receptor, cyclooxygenase (COX)-2, proapoptotic Bak and antiapoptotic Bcl-2 protein, as well as estrogen receptor (ER)-{alpha} and ER-ß mRNA were evaluated. Results were identical whether soy was fed for 1 or 2 generations. Soy decreased Bak and increased COX-2 and ER-{alpha} expression site-specifically in female mice. Vitamin D receptor protein was reduced only in males. In animals fed 0.04% dietary calcium, COX-2 protein was increased mainly in females, but supplementation of genistein to the diet lowered COX-2 expression significantly in both genders. Our results suggest that genistein counteracts the induction of a marker of colonic premalignancy by low nutritional calcium in both genders. However, soy itself enhances COX-2 and reduces Bak, but only in females. This suggests detrimental activity of an unknown component of soy triggered by a high-estrogen background.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Sporadic colorectal cancer has a latency time of at least 20 y until the disease manifests itself clinically. During this period a variety of factors, especially nutrition, will modulate progression in a positive or negative manner. Mouse models have been used to evaluate this in detail and to study the influence of nutritional factors on progression to colonic malignancy. Although mice consume a diet different from that of humans, certain components can be modulated to mimic human dietary deficiencies. These "stress diets" have much enhanced our knowledge about the damaging action of high fat, low dietary calcium, and low vitamin D on colon cells (1–3). Not only do these diets induce colonic hyperproliferation but they also favor expansion of an epithelial cell population containing atypical nuclei. After prolonged feeding, this results in dysplastic lesions and focal hyperplasia indicative of incipient tumorigenesis.

We (4,5) demonstrated the potential relevance of extrarenal vitamin D metabolism and of vitamin D receptor (VDR)6 expression for colorectal cancer incidence in human tissue. We postulated that enhanced expression and activity of colonic CYP27B1, the synthesizing 25-D3-1{alpha}-hydroxylase, and reduced expression of colonic CYP24, the 25-D3-24-hydroxylase, could lead to elevated levels of antimitotic, prodifferentiating, proapoptotic 1,25-dihydroxyvitamin D3 (1,25-D3) locally in the colonic mucosa. This in turn would counteract incipient neoplasia. Such a physiological defense mechanism would function only if sufficient serum levels of 25-hydroxyvitamin D3 were available, which would not be the case during vitamin D deficiency (6).

We (7) demonstrated that low dietary calcium (i.e., low fecal calcium content) will enhance the expression of the catabolic CYP24 in the colonic mucosa, which in turn could lead to reduced colonic accumulation of the antimitotic prodifferentiating 1,25-D3. We also demonstrated recently that estrogenic compounds such as 17ß-estradiol and genistein enhance expression of CYP27B1 in both colon and breast cancer cell lines in dependence of estrogen receptor (ER)-ß expression (D. Lechner, E. Bajna, H. Aldercreutz, and H. S. Cross, unpublished data). Phytoestrogens (i.e., plant-derived estrogens) apparently bind preferentially to ER-ß (8). Genistein is a prominent phytoestrogen in soybeans and red clover (9). We (10,11) showed that feeding soy or giving genistein once by gavage induced the expression of CYP27B1 and reduced that of CYP24. This could potentially optimize production of 1,25-D3, which, in turn, could reduce proliferation, increase apoptosis, and even reduce colonic inflammation, a well-recognized factor for progression toward malignancy.

The activity of various nutritional factors may affect segments of the colon in a differential as well as a gender-specific manner. Cancers of the right and left colon differ in their incidence and molecular genetics (12,13). Moreover, human sporadic colorectal cancer occurs significantly less frequently in women compared with age-matched men, and sex hormones may play a role in this etiology (14). Because it is increasingly recognized that sporadic cancer growth may be caused by an imbalance between proliferation and apoptosis, we wanted to investigate in a site- and gender-specific manner the effects of a diet containing low nutritional calcium and the modulation of premalignant markers by nutritional soy or the phytoestrogen genistein. To delineate potentially adverse effects of long-term soy consumption, we fed mice for 1 and 2 generations.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Materials. Genistein (5 g) was kindly provided by DSM, Basel, Switzerland.

C57BL/6 mice were housed at the Centre for Laboratory Animal Care at the University of Vienna in a contained environment. Mice were weaned at age 3 wk, given free access to either a standard diet (based on AIN76A) or a soy diet (AIN76A containing 200 g/kg extracted soybean meal instead of casein). Another set of animals was fed a standard diet containing normal levels (0.5%) or low levels (0.04%) of calcium, with or without 0.04% genistein. Calcium levels were chosen because they represent intakes equivalent to high and low nutrient density for humans (3). Mice were anesthetized and then killed by cervical dislocation at age 13–14 wk, and tissue samples were collected. Treatment groups consisted of at least 6 animals. The study protocols were reviewed and approved by the Institutional Committee of Animal Experimentation of the University of Vienna Medical School and by the Austrian Ministry of Science and Education.

    Western blot analysis. Western blot analysis was performed as described previously (7). Total proteins extracted from snap-frozen ascending and descending colon of mice were separated by 12% SDS-polyacrylamide gel electrophoresis and subsequently blotted to a nitrocellulose membrane. The membranes were incubated overnight with the following antibodies: rabbit anti-Bak (Upstate Biotechnology), goat anti-Bcl-2 (R&D Systems), rabbit anti-VDR (Santa Cruz), and goat anti-COX-2 (Santa Cruz). Horseradish peroxidase-conjugated secondary antibodies (Amersham Life Sciences) were used. Subsequent detection was performed with the SuperSignal CL-HRP Substrate system (Pierce). Mucosal homogenate derived from untreated mice was used in every blot as an internal control. Bands were evaluated by densitometry with a video camera imaging system (Herolab).

    Semiquantitative RT-PCR. For analysis of ER-{alpha} and -ß mRNA expression by RT-PCR, total RNA was extracted from snap-frozen mouse ascending and descending colon with TRIzol reagent (Invitrogen). For synthesis of single-stranded cDNA, 2 µg total RNA was used (Superscript II kit, Invitrogen). PCR conditions were as follows: 15 s at 94°C, 30 s at 60°C, and 1 min at 72°C for 35 cycles for both ER-{alpha} and ER-ß, using the GeneAmp PCR System 9600 (PE Applied Biosystems); ER-{alpha} sense 5'-TCC TAA CTT GCT CCT GGA CAG G-3' and antisense 5'-CAG GAG CAG GTC ATA GAG GGG-3'; and ER-ß sense 5'-TAG CCA CCC ACT GCC AAT CAT C-3', antisense 5'-CCC ACA CCT TTC TCT CCT GGA TC-3'. PCR products were checked for correct size and fragment length by multiple digestions with restriction enzymes. Gels were scanned and analyzed with a video camera imaging system (Herolab); band density was measured under UV light.

    Statistical analyses. Data are presented as means ± SD. Student's t test was used for statistical group analysis. P-values below 0.05 were considered as statistically significant.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Soy feeding of male and female mice for 1 or 2 generations. We evaluated the expression of apoptotic markers Bak (proapoptotic) and Bcl-2 (antiapoptotic), COX-2 as a marker of inflammation, and VDR by Western blotting. Animals were fed 20% soy either for 2.5 mo after weaning (first generation) or during reproduction, and the resultant pups were fed the same diet for 2.5 mo after weaning (second generation). Control animals were fed casein as principal source of protein. We did not observe altered reproductive behavior in the second-generation animals, nor did marker expression vary from that observed in first-generation animals. Because of this, data are presented together.

    Apoptosis. Measurement of the balance between proapoptotic and antiapoptotic markers is frequently considered to be the best indicator of actual apoptotic events. Figure 1 shows that the proapoptotic marker Bak is equally expressed in the proximal and distal colon in both male and female mice. Although the antiapoptotic marker is very prominent in the proximal colon, it is barely present in the distal colon. The net result would be more apoptotic potential in the distal colon in both genders.


Figure 1
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  		Figure 1  Evaluation of Bak and Bcl-2 protein expression in ascending (CA) (proximal) and descending colon (CD) (distal) of male and female mice by immunoblotting. Densitometric data were calculated as percentage of mucosal homogenates derived from untreated mice used in every blot as internal control. Results are expressed as means ± SD.

 
In male mice, soy feeding had no effect on Bak expression in either the proximal or the distal colon; in the female mouse expression was significantly reduced but only in the proximal colon (Fig. 2 A). Bcl-2 expression was not affected by soy feeding (not shown).


Figure 2
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  		Figure 2  Effect of soy feeding on protein expression of (A) Bak, (B) COX-2, and (C) VDR in ascending (CA) and descending colon (CD) in male and female mice by Western blot. Bak, COX-2, and VDR protein expression was quantified densitometrically. Representative immunoblots are shown. Data were calculated as percentage of mucosal homogenate from untreated mice used in every blot as internal control. Results are expressed as means ± SD; *P < 0.05%; ***P < 0.001%.

 
    COX-2 expression. COX-2 is an inducible enzyme that regulates prostaglandin synthesis, which is overexpressed at sites of inflammation and frequently in colorectal cancer. Mechanistic studies indicate that COX-2 may be involved in resistance to apoptosis (15). When we evaluated expression of COX-2 protein by immunoblotting, we observed that soy feeding significantly elevated this inflammatory marker in the proximal colon of female mice (Fig. 2 B).

    VDR expression. We (4,16) showed previously that in human colon tissue VDR mRNA expression is up-regulated during hyperproliferation and advancing malignancy, potentially to mediate higher antimitotic activity of vitamin D. Soy, however, is an antimitotic nutritional substance for the mouse colon: it down-regulates proliferating cell nuclear antigen expression stimulated by low dietary calcium (11). When we investigated modulation of colonic VDR protein expression by soy feeding in a gender- and site-specific manner, it became apparent that it affected the proximal as well as the distal colon. VDR expression was down-regulated but only in males (Fig. 2 C). The detrimental effects of soy feeding in females (i.e., COX-2 up-regulation and Bak down-regulation, both in the proximal colon) prompted us to investigate modulation of ERs.

    ER-{alpha} and ER-ß expression. We evaluated ER-{alpha} and -ß expression by RT-PCR (Fig. 3). Although expression of ER-ß (Fig. 3 B), the preferential receptor for phytoestrogens, is not altered by soy feeding in either males or females, ER-{alpha} mRNA is elevated in females (Fig. 3 A). This occurs in the proximal colon only, the site where COX-2 is elevated and Bak expression is reduced.


Figure 3
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  		Figure 3  Effect of soy feeding on mRNA expression of (A) ER-{alpha} and (B) ER-ß in ascending (CA) and descending colon (CD) in male and female mice. Data were determined by RT-PCR and are expressed as means ± SD. **P < 0.01%.

 
    Effect of genistein on low-calcium diet-induced COX-2 expression. We (11) demonstrated previously that genistein may be one of the antitumorigenic substances present in soybeans, at least with respect to regulation of proliferation and of vitamin D synthesis. Elevated 1,25-D3 levels might have an enhanced antiinflammatory effect. When we fed mice 0.5% calcium, supplementation with genistein did not influence COX-2 expression. Low dietary calcium elevated expression of COX-2 protein in all colonic segments but mainly in females. When mice were fed low dietary calcium together with genistein, COX-2 expression was significantly reduced in both genders and in all colonic segments (Fig. 4).


Figure 4
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  		Figure 4  Effect of low (0.04%) versus high (0.5%) dietary calcium and of genistein supplementation on expression of COX-2 in ascending (CA) and descending colon (CD) of male (A) and female (B) mice evaluated by immunoblotting. Data were calculated as percentage of mucosal homogenate derived from untreated mice used in every blot as an internal control. Results are expressed as means ± SD; *P < 0.05%.

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
Evidence is growing that a number of different classes of food constituents can regulate cell proliferation and cell death in colorectal crypts (17,18). Apoptotic events are either initiated via activation of a receptor by an extracellular ligand such as Fas or triggered by various types of cellular stress including DNA damage. A key signaling event is the release of cytochrome c from the mitochondria into the cytosol. Proteins of the Bcl-2 family can stimulate or retard the release of cytochrome c. This family includes Bax and Bak as proapoptotic proteins and Bcl-2, Bcl-xl, and Bcl-w as antiapoptotic proteins. In the mouse colon, basal apoptotic levels are lower than those in the small intestine, and this appears to be associated with high expression of antiapoptotic proteins such as Bcl-w (19).

Suppression of apoptosis may favor progression into the adenoma-carcinoma sequence. Down-regulation of apoptosis may be caused by loss of functional proapoptotic genes or adaptation to a chronic state of mucosal inflammation (20). Evidence for this was provided with nonsteroidal antiinflammatory drugs and the specific COX-2 inhibitor Celecoxib (21). Because genistein can induce apoptosis and can suppress certain tumor-promoting proteins such as COX-2 (22), it may have potential as a chemotherapeutic agent.

Soy-consuming Asian populations have been suggested to be protected not only against breast and prostate cancer incidence but also against colorectal tumors. These populations are exposed to phytoestrogens from birth, which may protect them against the growth-promoting action of sex hormones. In contrast, intermittent exposure to soy products such as those used for relief of postmenopausal symptoms in Western countries could have potentially hazardous effects. Whether the ingestion of soy constituents with estrogenic activity in addition to the presence of high serum estrogen levels in premenopausal women is harmful should be questioned.

The present study was therefore initiated to evaluate in vivo, in a mouse model, whether soy feeding (20% soybean meal added to an AIN76 diet instead of casein) would have differential effects on females and males because of their different estrogenic background. In addition, we wanted to study whether long-term exposure to high dietary soy over 2 generations would detrimentally or beneficially affect markers of apoptosis, proliferation, and inflammation.

Our data demonstrate that in the proximal colon there is a high prevalence of antiapoptotic Bcl-2 expression, whereas in the distal colon Bcl-2 is hardly detectable (Fig. 1). The proapoptotic Bak protein is distributed equally in proximal and distal colon. Dietary soy effects were similar in first- and second-generation mice. In male mice neither proapoptotic Bak nor antiapoptotic Bcl-2 or COX-2 was altered by high soy nutrition. In females, however, and solely in the proximal colon, Bak was highly significantly reduced, and COX-2 expression was increased, whereas Bcl-2 levels did not change. In parallel, we found an increase in ER-{alpha} mRNA expression, whereas ER-ß was not altered. This suggests that, because of the high estrogenic background in the females, soy feeding (i.e., a high intake of phytoestrogens) could detrimentally affect the colon mucosa via up-regulation of ER-{alpha}, down-regulation of apoptosis, and induction of an inflammatory marker.

Estrogenic substances were shown to enhance expression of VDR in vivo (23). Although this could be interpreted as an event that would facilitate the antimitotic activity of 1,25-D3, it could also be the consequence of a growth-stimulating action by estrogen: it is well recognized that during hyperproliferation and progression into early malignancy, expression of the VDR is enhanced in the human colon mucosa (4). In any case, most studies have shown high expression of VDR in colonic crypts; thus, it is unlikely that amounts of this receptor could be limiting under normal circumstances (24). In our experimental model soy down-regulated VDR levels but only in males: this may reflect the antiproliferative effect of soy on the colonic mucosa when serum estrogen levels are low (25).

To evaluate the active constituent present in soy, we exposed male and female mice to 0.04% dietary calcium with and without 0.04% genistein for 2.5 mo. For an average food intake per mouse of 5 g/d, this would be equivalent to a genistein intake of 7.4 µmol/d. This is a considerable amount in view of the fact that human serum genistein levels in populations consuming soy habitually are rarely above 1 µmol/L.

Although low dietary calcium increased COX-2 protein expression in both males and females, the increase was significant only in females. Genistein, however, consistently and significantly lowered COX-2 expression induced by low calcium in both the proximal and distal colon and in both genders. This suggests that genistein, even at high concentrations, has a beneficial effect on the colon mucosa and that the enhanced expression of COX-2 caused by prolonged soy feeding of females could be linked to another constituent present in soy.

In conclusion, our data indicate that, at least for the colon, feeding soy over 2 generations is no more harmful than for 1 generation. Although genistein appears to be a phytoestrogen with potentially beneficial action on the colon even at high concentrations because it modifies inflammatory markers and apoptosis as well as the colonic vitamin D system (26), feeding high amounts of soy could introduce an unknown soy constituent that, with a high estrogenic serum background, could be harmful in vivo.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented as part of the International Research Conference on Food, Nutrition, and Cancer held in Washington, DC, July 13–14, 2006. This conference was organized by the American Institute for Cancer Research and the World Cancer Research Fund International and sponsored by (in alphabetical order) the California Walnut Commission; Campbell Soup Company; Cranberry Institute; Hormel Institute; IP-6 International, Inc.; Kyushu University, Japan Graduate School of Agriculture; National Fisheries Institute; and United Soybean Board. Guest editors for this symposium were Vay Liang W. Go, Susan Higginbotham, and Ivana Vucenik. Guest Editor Disclosure: V.L.W. Go, no relationships to disclose; S. Higginbotham and I. Vucenik are employed by the conference sponsor, the American Institute for Cancer Research. Back

2 Author Disclosure: No relationships to disclose. Back

3 Financially supported by AICR grant 03B031. Back

6 Abbreviations used: 1,25-D3, 1,25-dihydroxyvitamin D3; COX, cyclooxygenase; ER, estrogen receptor; VDR, vitamin D receptor. Back


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

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