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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2080-2085
Copyright © 1999 by The Endocrine Society

Original Studies

Loss of Estrogen Inactivation in Colonic Cancer

Mark A. English1, Kate F. Kane, Neil Cruickshank, Michael J. S. Langman, Paul M. Stewart2 and Martin Hewison

Division of Medical Sciences, The Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, United Kingdom

Address all correspondence and requests for reprints to: Dr. Martin Hewison, Department of Medicine, The Queen Elizabeth Hospital, The University of Birmingham, Birmingham B15 2TH, United Kingdom. E-mail: m.hewison{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Age and sex differences in the incidence of colonic cancer, together with epidemiological data on patients taking hormone replacement therapy, suggest the involvement of estrogens. Analogous to the role of aromatase in breast cancer, we postulated that steroid metabolism within the colon itself may be a crucial mechanism in regulating tissue exposure to estrogens. We have characterized expression of aromatase (responsible for converting C19 androgens to C18 estrogens) and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) [responsible for interconversion of active estradiol (E2) to less potent estrone (E1)] in normal and neoplastic human colon from 24 patients undergoing tumor resection. Aromatase activity was similar in homogenates from normal mucosa, tissue adjacent to tumors, and the tumors themselves. Analysis of 17ß-HSD activity indicated that the predominant activity was oxidative (E2 to E1), and this conversion was significantly lower in colonic tumors [444 (90–1735); median (95% confidence interval) pmol/mg protein·h], compared with normal mucosa [1709 (415–13828), P < 0.001]. Northern blot analyses indicated expression of messenger RNAs (mRNAs) for the type 2 and 4 isozymes of 17ß-HSD in normal colon; messenger RNA for 17ß-HSD 4 was significantly lower in tumor tissue [0.75 ± 0.22 (mean ± SD) arbitrary U vs. 0.43 ± 0.17, P < 0.01]. Studies in vitro, using three colonic cancer cell lines, indicated that there was an inverse correlation between 17ß-HSD oxidative activity and the rate of cell proliferation. In addition, E1, but not E2, was shown to significantly decrease proliferation when added exogenously to the colonic epithelial cell line, SW620 cells. Colonic mucosa can regulate estrogen hormone action in an intracrine fashion. The loss of estrogen inactivation may be an important mechanism in the pathogenesis of colonic cancer.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE EPIDEMIOLOGY of large bowel cancer suggests a role for sex steroids in its development. Females less than 55 yr of age show higher frequencies of colonic cancer, compared with males; but after the menopause, cancer of the colon becomes more common in men (1, 2). These findings would suggest that exposure to the active estrogen, estradiol (E2), is associated with a higher incidence of colonic cancer. By contrast, estrogen treatment in the form of hormone replacement therapy (HRT) seems to protect against colonic cancer (3, 4, 5), though it is important to stress that estrone (E1), and not E2, is the major constituent of HRT regimes such as Premarin and Prempak C (Wyeth-Ayerst Pharmaceuticals, Inc., Philadelphia, PA)

Tissue factors that might underlie hormone responsiveness in the colon are poorly understood. Several reports have documented expression of sex hormone receptors in gastrointestinal tumors and cell lines, although the reported levels of estrogen receptors (ER) and progesterone receptors seem to vary considerably (6). Studies from our group have demonstrated the presence of ER in normal and neoplastic mucosa, as well as highlighting differential responses to E2 in premalignant and malignant cell lines (7, 8). More recently, estrogen-dependent growth of human-derived colonic carcinoma cell lines has been shown to be mediated via ER (9). These findings have emphasized a role for sex hormones and their receptors in modulating colonic cell function.

In common with other peripheral tissues, it is likely that the concentrations of active androgens and estrogens in the colon will be regulated by locally expressed metabolizing enzymes. Peripheral metabolism of androgens and estrogens is largely dependent on the enzyme aromatase (10) and the multiple isoenzymes of 17ß-hydroxysteroid dehydrogenase (17ß-HSD) (11, 12). Local activity of both aromatase and 17ß-HSD have been shown to make an important contribution to the high estrogen concentrations found in some tumor tissues. In breast carcinomas for example, increased aromatization of C19 androgens to C18 estrogens by the tumor tissue itself is thought to be a major factor in the differentiation, proliferation, and progression of breast carcinomas (13, 14, 15). To clarify the contribution of local steroid metabolism to the pathophysiology of colon cancer, we have carried out similar studies analyzing the expression and activity of aromatase and 17ß-HSD enzymes in the colon.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Tissue

Colonic tumor specimens from 24 patients (10 male) with colorectal cancer were analyzed, together with paired normal mucosa (10 cm from tumor) and mucosa adjacent to the tumor. The mean age of the patients was 72.2 ± 3.3 yr, and only 3 patients (all male) were less than 55 yr of age. Of the tumors, 7 were well differentiated, 11 were moderately differentiated, and 3 were poorly differentiated; 3 were adenomas. Tumor and mucosal samples were taken immediately after surgical colon resection and either snap frozen, using liquid nitrogen, or placed in 0.154 M KCl buffer and homogenized. Homogenates were centrifuged at 13,000 rpm for 5 min at 4 C, a protein assay (Bio-Rad kit, Hemel Hempstead, UK) was carried out on the supernatant, and 500-µL aliquots (1 mg protein/mL) were stored at -70 C.

Analysis of aromatase and 17ß-HSD activity

Interconversion of androstenedione (A), testosterone (T), E1, and E2 was measured using either [1,2,6,7]-3H-A (87 Ci/mmol, NEN Life Science Products, Hounslaw, UK), [1,2,6,7]-3H-E1 (100 Ci/mmol, Amersham-Pharmacia Biotech, Rainham, UK), or [1,2,6,7]-3H-E2 (80 Ci/mmol, Amersham, UK) as substrates for metabolic assays. Assays were carried out in quadruplicate on colon homogenates (200 µg protein/mL for A and E1 as substrate; 100 µg protein/mL for E2 as substrate), incubated at 37 C in a shaking water bath with 40 nM A (60 min) or 100 nM E1 (60 min) or 100 nM E2 (10 min). Assays were carried out in standard 0.154 M KCl buffer, which also contained either 1 mM nicotinamide adenine dinucleotide phosphate (reductive) (NADPH) (substrate = A and E1) or 0.5 mM nicotinamide adenine dincleotide (oxidative) (NAD+) (substrate = E2) as cofactors for aromatase and 17ß-HSD enzymes. At the above substrate concentrations and time periods, reaction rates were linear. The reaction was terminated by the addition of 2.5 mL chloroform, and steroids were extracted, and the organic phase was dried down under nitrogen. Each sample was resuspended in 50 µL chloroform and separated by thin-layer chromatography using chloroform:ethyl acetate (80:20 vol/vol) as mobile phase. Fractional conversion of tritiated steroid was measured on a Bioscan, Inc. (Washington, DC) System 200 imaging thin-layer chromatography plate scanner and expressed as pmol E1, E2, or T produced/mg protein·h.

Northern analysis of 17ßHSD messenger RNA (mRNA) expression

Total RNA was extracted from normal mucosa, mucosa adjacent to tumor, and tumorous tissue, using a single-step method modified from Chomczynski et al. (16) (RNazol, AMS Biotechnology, Witney, UK). Poly A mRNA was prepared from each total RNA sample using a PolyATtract kit magnetic bead system (Promega UK Ltd, Southampton, UK). Aliquots (1 µg) of poly A mRNA from colon samples were separated by denaturing gel electrophoresis and were blotted onto Hybond N-plus nitrocellulose filters. Northern blots were then probed for 17ß-HSD types 1–4 using methods described previously (17). After hybridization for 16 h at 65 C, filters were washed to a final stringency of 0.1x standard sodium citrate buffer at 65 C, and filters were exposed to Dupont Cronex film NEN Life Science Products before development of autoradiographs. Scanning densitometry was carried out on autoradiographs exposed for the same period of time (24 h). Data for each RNA analysis were normalized as a ratio of densitometry values for ß-actin and reported as arbitrary relative densitometry units (mean ± SD, n = 8).

Cell culture

Human colonic cancer cell lines (SW620, Caco-2, and HT29) were seeded at equal density and maintained in phenol red-free DMEM (Gibco BRL, Paisley, UK) supplemented with 5% FCS. Quantification of changes in colonic cell proliferation were undertaken by determining nuclear incorporation of 3H-thymidine (80Ci/mmol, Amersham). Analysis of estrogen metabolism in the cell lines was carried out using protocols described above for patient colon tissue.

Statistical analysis

Data for aromatase and 17ß-HSD activities in colonic homogenates are presented as median [95% confidence interval (CI)], and statistical analysis was undertaken using the Mann-Whitney U test. Data for proliferation of colonic cancer cells and Northern blot densitometry are presented as mean ± SD, and statistical significance was assessed using a Student’s t test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Studies using 3H-A as a potential substrate for both aromatase and 17ß-HSD activities indicated that the predominant metabolism in normal colonic mucosal tissue was A to T (17ß-HSD) rather than A to E1 (aromatase) (Fig. 1Go, A and B). In addition, small amounts of E2 were generated from A, suggesting a net effect of both 17ß-HSD and aromatase (Fig. 1CGo). Aromatase activity (A to E1) was similar in normal mucosal tissue [5.8 (1.3–12.4) pmol/mg protein/h], compared with tumors [5.5 (1.6–18.7)]. However, 17ß-HSD activity (A to T) was significantly decreased in tumors [4.6 (0.6–17.9) pmol/mg protein·h], compared with either normal tissue [11.1 (2.6–51.0), P < 0.001] or tissue adjacent to tumor [10.1 (2.8–34.1), P < 0.005] (Fig. 1BGo). Decreased 17ß-HSD activity was also reflected in data for conversion of A to E2 that was significantly lower in tumor tissue [0.37 (0.00–1.26)], compared with normal mucosa [0.77 (0.00–2.20) pmol/mg protein·h, P < 0.05] (Fig. 1CGo).



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  		Figure 1. Metabolism of 3H-androstenedione (A) in normal human colon, colon tissue adjacent to tumor, and tumor tissue. Samples were taken from 24 patients undergoing tumor resection (10 male, 14 female). Data are expressed as pmol product/mg protein/·h [bar = median values (95% CI)]. Panel A, Conversion of A to E1; panel B, conversion of A to T; panel C, conversion of A to E2. Despite unchanged levels of aromatase activity (panel A), conversion of A to T (panel B) and conversion of A to E2 (Panel C) were significantly reduced in tumor homogenates, suggesting loss of 17ß-HSD activity.

 
Further studies of 17ß-HSD activity indicated that conversion of E2 to E1 in normal mucosa in the presence of NAD+ (oxidative) [1709 (415–13828) pmol/mg protein·h] was significantly higher than E1 to E2 in the presence of nicotinamide adenine dinucleotide phosphate (reductive) [28.8 (0.1–53.0), P < 0.001]. No reductive or oxidative metabolism was observed in the absence of exogenously added cofactors, and no conversion of E2 to E1 was observed in the presence of nicotinamide adenine dinucleotide phosphate (oxidative) (data not shown). Kinetic analysis of oxidative 17ß-HSD activity in normal mucosa revealed an apparent affinity constant (Km) for E2 of 0.75 µM with a maximal rate (Vmax) of 7 nmol/mg protein·h) (data not shown). There was a significant reduction in E2-to-E1 conversion in colon tumor samples [444 (90–1735) pmol/mg protein·h], when compared with either normal mucosal tissue [1709 (415–13828), P < 0.001] or tissue adjacent to the tumor [1217 (470–4334), P < 0.001] (Fig. 2Go). Although there was considerable interindividual variability in 17ß-HSD oxidative activity, the same trend of activity (normal > adjacent > tumor) was observed in 23 of 24 patients studied (Fig. 3AGo). When males and females were analyzed separately, similar significant changes were seen, and there were no differences between male and female values (data not shown). In addition, we were unable to determine any correlation between tumor status (well differentiated vs. poorly differentiated, or carcinoma vs. adenoma) and the level of 17ß-HSD activity (data not shown). To evaluate specificity of the observed changes in 17ß-HSD activity, parallel analysis of the related NAD-dependent enzyme, 11ß-HSD type 2 (18), revealed no significant differences in oxidative metabolism of cortisol to cortisone in normal mucosa (11.1 pmol cortisone/mg protein·h), compared with adjacent-to-tumor (11.9) and tumor samples (8.8) (all median values n = 24) (Fig. 3BGo).



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  		Figure 2. Conversion of E2 to E1 in homogenates of normal human colon, colon tissue adjacent to tumor, and tumor tissue. Data (n = 24 subjects) are presented as conversion values for each subject and are expressed as pmol product/mg protein·h [bar = median values (95% CI)]. 17ß-HSD activity (E2 to E1 conversion) was significantly lower in tumor tissue, when compared with either normal colon or tissue adjacent to a tumor.

 


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  		Figure 3. Comparison of estrogen and glucocorticoid metabolism in colonic tumors. A, Conversion of E2 to E1 in colon homogenates, presented as pmol E1 produced/h·mg protein from paired data sets of normal colon mucosa and colon tumor homogenates (n = 24 subjects). Significant reduction in oxidative 17ß-HSD activity is shown, after the pattern normal>>tumor. In 23 of 24 patients, 17ß-HSD activity was reduced in tumor homogenates. B, Conversion of cortisol to cortisone (11ß-HSD activity) in paired sets of normal colon mucosa and colon tumor homogenates (n = 24 subjects). No significant change in capacity to metabolize cortisol was observed in normal mucosae vs. tumor homogenates.

 
Northern analyses suggested the predominant expression of 17ß-HSD type 2 and type 4 mRNA (Fig. 4Go); the type 1 and type 3 isoforms were undetectable using this method of detection. To demonstrate a band corresponding to 17ß-HSD 2, filters were exposed to autoradiograph film for three-times as long as filters probed with 17ß-HSD 4 (Fig. 4AGo). Quantitative analysis of 17ß-HSD mRNA revealed that levels of 17ß-HSD type 4 mRNA were approximately seven times higher than those observed for 17ß-HSD type 2. Although no differences in 17ß-HSD 2 mRNA were observed, there was a significant reduction in the levels of 17ß-HSD 4 mRNA expression in colon tumors [0.43 ± 0.17 (mean arbitrary units ± SD)], when compared with normal mucosa (0.75 ± 0.22, P < 0.01) (Fig. 4BGo).



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  		Figure 4. Analysis of 17ß-HSD isozyme mRNA expression in human colon. Panel A, Typical Northern blot, showing expression of 17ß-HSD 2 and 4 mRNA in normal mucosal tissue (N), mucosa adjacent to tumor (A), and tumor itself (T). Loading on Northern blots was normalized using a probe for ß-actin. B, Quantitative analysis of 17ß-HSD 2 and 4 mRNA expression by densitometry. Values (mean ± SD, n = 8) were normalized, relative to ß-actin mRNA expression. *, Significantly different from normal mucosal tissue, P < 0.01).

 
Finally, using three colonic cancer cell lines (Caco-2, SW620 and HT-29), an inverse correlation was observed between the level of E2-to-E1 metabolism and rate of cell proliferation. Both aromatase and the much higher oxidative 17ß-HSD activities were highest in Caco-2 cells, which showed the lowest rate of 3H-thymidine incorporation (Fig. 5Go). Further studies of SW620 cells were carried out to determine the effects of exogenously added sex hormones on 3H-thymidine incorporation. Of the various treatments used, only E1 (at 100 nM) was able to significantly inhibit cell proliferation, when compared with cells treated with vehicle alone (P < 0.05) or when compared with cells treated with E2 (P < 0.05) (Fig. 6Go).



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  		Figure 5. Comparison between aromatase activity (A), oxidative 17ß-HSD activity (B), and DNA synthesis (C) in colonic epithelial cell lines Caco-2, SW620, and HT-29. Rates of cell proliferation, as measured by DNA incorporation of 3H-thymidine, were highest in cells with the lowest conversion of E2 to E1. Cpm, counts per minute.

 


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  		Figure 6. Effect of treatment with sex steroids and corticosteroids on proliferation of SW620 cells. Partially confluent cells were treated with 100 nM progesterone, dexamethasone, E1, E2, testosterone, and dihydrotestosterone (DHT) for 48 h in phenol red-free medium. Cell proliferation was assessed by nuclear incorporation of 3H-thymidine. Values are mean ± SD (n = 6). *, Significantly different from vehicle-treated cells, P < 0.05; **, significantly different from E2-treated cells, P < 0.05. Cpm, counts per minute.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The efficient maintenance of circulating levels of sex hormones in adults is dependent upon a complex network of steroidogenic enzymes located in the adrenals and gonads. In addition, it is now established that the peripheral metabolism of sex steroids contributes to their action at an autocrine, intracrine, paracrine, and endocrine level (19, 20). The widespread tissue distribution of aromatase and 17ß-HSD isozymes suggests a role for these enzymes as local modulators of sex steroid hormone action in peripheral tissues; to support this concept, our recent studies have highlighted the functional relevance of aromatase and 17ß-HSD expression in keratinocytes (17) and osteoblasts (21). Others have characterized these enzymes in adipose tissue (22, 23). These and other studies have promoted the concept of intracrine regulation of local steroidogenesis as an important component of tissue physiology (20). Specific attention has focused on a role for intracrinology in the pathophysiology of hormone-sensitive cancers such as cancers of the prostate, uterus, and breast (13, 14, 15, 20). In this study, we have assessed the expression and activity of aromatase and 17ß-HSD in normal and neoplastic colon tissue. Data show, for the first time, that colonic mucosal tissue has a high capacity for inactivation of E2 to E1 and that this metabolism is significantly decreased in neoplastic tissue. Preservation of conversion of cortisol to cortisone metabolism via 11ß-HSD type 2 in colon tumor tissue indicates that our results are unlikely to reflect nonspecific loss of enzyme activity in, for example, necrotic tissue, or an alteration in endogenous cofactor concentrations. Aromatase activity (using either 3H-A or 3H-1ßA as substrate) was lower than that described previously for breast adipose tissue (13, 14, 15); but, in contrast to studies of breast carcinomas, we were unable to determine any changes in aromatase activity in neoplastic colon.

Six isoforms of 17ß-HSD have, so far, been cloned and characterized; and these show considerable sequence variation, as well as substrate and cofactor specificity (11, 12). Data presented in this study indicate that, although the predominant 17ß-HSD activity in the colon was oxidative metabolism of E2 to E1, lower levels of A-to-T metabolism, as well as E1-to-E2 conversion, were also detectable. This, together with the Northern analysis data suggests that the principal enzymes involved in colonic estrogen metabolism are 17ß-HSD 2 and 17ß-HSD 4. Both of these isozymes show predominant oxidative activity but are also able to carry out weak reductive metabolism and may use several substrates for this activity. Alternatively, because we were unable to detect significant levels of mRNA for 17ß-HSD 3, the low levels of reductive estrogen metabolism in the colon may be caused by expression of the recently cloned 17ß-HSD 5 (24). This particular isozyme shows predominant A-to-T conversion but has proved difficult to characterize in tissue preparations because of its lability and a high degree of amino acid identity with 17ß-HSD 1 and 3 (24). It remains to be determined whether 17ß-HSD 4 is the principal source of E2 metabolism in the colon and whether decreased mRNA expression for this isozyme is the principal cause of lower 17ß-HSD activity in colonic cancers. The enzyme is a member of the short-chain alcohol dehydrogenase family but also has fatty acid metabolism and sterol carrier activities (25). Importantly, the peroxisomal location and ubiquitous expression of 17ß-HSD 4 suggests a role in modulating cell proliferation. The expression of this enzyme in leukocytes has previously been shown to be stimulated by differentiating agents (26), and we have recently demonstrated abnormal expression of 17ß-HSD 4 in cells with elevated levels of DNA synthesis (27). The type 2 form of 17ß-HSD may also make a significant contribution to estrogen metabolism in the colon, even though mRNA levels for this isozyme were relatively low. Recent studies in the mouse, using in situ hybridization, suggest that 17ß-HSD 2 mRNA expression is restricted to the surface epithelium of the colon (28).

The importance of estrogens in the pathogenesis of colon cancer is illustrated by epidemiological data showing an increased male to female ratio of colonic cancer incidence with advancing age (1, 2). Furthermore, women taking HRT may be at reduced risk of developing colonic cancer (3, 4, 5). A greater cancer incidence in younger women suggests that estrogen exposure may be predisposing, whereas estrogen, in the form of HRT, seems to be protective. This paradox is similar to the age-related variations that have been described for breast cancer. A possible explanation for these differences in responses is that one of the principal prescribed HRTs (Premarin/Prempak C) contains delta-8-E1 sulphate, and not E2. Although a clear relationship between the estrogen composition of HRT regimes and protection against colon cancer has yet to be fully described, analysis of a large prospective cohort in the United States showed that Premarin offered the most significant protection against colonic cancer (3, 4, 5). Orally administered E1, therefore, may have considerably different effects on the colon, compared with E2. Di Domenico et al. demonstrated a small, but significant, rise in the proliferation of Caco-2 cells after treatment with E2, whereas E1 inhibited cell proliferation (9). In studies using SW620 cells, we demonstrated a similar inhibition of proliferation after treatment with 100 nM E1, which was not observed with E2 or other sex hormones. Previous results from our group, using keratinocytes (17) and monocytes (29), also have demonstrated antiproliferative effects of E1, suggesting that it is no longer accurate to refer to E1 as an inactive estrogen. The precise mechanism by which E1 is able to modulate colonic cell proliferation remains to be determined. Several recent reports have indicated that antiestrogen compounds, such as tamoxifen, inhibit colonic cancer cell proliferation in vitro, although none of the cell lines used in these studies seemed to express ER (30, 31). It is therefore possible to speculate that effects of estrogen-like molecules on colon cancer cells may, in part, be mediated via binding to nonclassical ER. Further investigation will be required to fully elucidate this mechanism. Data presented here show clearly that there is a close relationship between the capacity to generate E1 via 17ß-HSD and the rate of cell proliferation. It is possible, therefore, that epidemiological data on the risk of colonic cancer are attributable to the beneficial effects of E1, together with deleterious effects of E2. The loss of 17ß-HSD activity, highlighted in this study, could result in a significant increase in the E2/E1 ratio within neoplastic colon tissue, and it may be an important mechanism in the underlying pathogenesis of colonic cancer.


   Acknowledgments
 
We would like to thank Dr. D. Morton (University of Birmingham) for help in organizing tissue collection, and Dr. W. E. Rainey (Southwestern Medical Center, Dallas) for advice regarding analysis of 17ß-HSD mRNA expression.


   Footnotes
 
1 Recipient of a British Digestive Foundation Hunt Memorial/Hurst Centenary Grant. Back

2 An Medical Research Council Senior Clinical Fellow. Back

Received January 21, 1999.

Revised March 4, 1999.

Accepted March 11, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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