Loss of Estrogen Inactivation in Colonic Cancer

English, M A; Kane, Kate; Cruickshank, Neil; Langman, M. J. S.; Stewart, Paul M.; Hewison, Martin

doi:10.1210/jcem.84.6.5772

Cited by 55 publications

(40 citation statements)

References 27 publications

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“…Initial enzyme activity studies revealed a similar pattern of oestrogen metabolism to that previously described in primary colonic mucosae (English et al, 1999). In Caco-2, SW620 and HT-29 cells the predominant 17β-HSD activity was oxidative conversion of E 2 to E 1 .…”

Section: Analysis Of 17β-hsd Activity In Vitrosupporting

confidence: 67%

“…Analogous to well documented studies in breast cancer (O'Neill et al, 1988;Sasano et al, 1996), we have postulated that local steroid metabolism in the colon may play a key role in modulating the effects of oestrogens by determining the tissue availability of active E 2 . In recent studies using tissue biopsies we have shown that the normal colonic mucosa has a high capacity for metabolism of E 2 (English et al, 1999). Furthermore, the predominant metabolic activity, inactivation of E 2 to oestrone (E 1 ), was significantly decreased in paired tumour biopsies.…”

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confidence: 99%

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Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

et al. 2000

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Summary Epidemiological data suggest that oestrogen contributes to the aetiology of colonic cancer. Furthermore, recent studies have suggested that local hormone metabolism may play a key role in determining colonic responsiveness to oestrogen. To further clarify this mechanism we have characterized the expression and regulation of isozymes of 17β-hydroxysteroid dehydrogenase (17β-HSD) in vitro and in situ. Immunohistochemistry was used to confirm expression of the type 2 and 4 isozymes of 17β-HSD (17β-HSD2 and 4) in normal colonic epithelial cells. Parallel studies suggested that both isozymes were abnormally expressed in colonic tumours and this was confirmed by Western blot analyses. Abnormal expression of 17β-HSD2 and 4 proteins was also observed in Caco-2, HT-29 and SW620 colonic cancer cell lines, although the overall pattern of oestrogen metabolism in these cells was similar to that seen in primary colonic mucosal tissue. The predominant activity (conversion of oestradiol to oestrone) was highest in Caco-2>SW620>HT-29, which correlated inversely with the rate of proliferation of the cell lines. Regulatory studies using SW620 cells indicated that the most potent stimulator of oestradiol to oestrone inactivation was the antiproliferative agent 1,25-dihydroxyvitamin D 3 (1,25D 3 ), whilst oestradiol itself inhibited 17β-HSD activity. Both oestradiol and 1,25D 3 decreased mRNA for 17β-HSD2 and 4. Data indicate that the high capacity for inactivation of oestrogens in the colon is associated with the presence of 17β-HSD2 and 4 in epithelial cells. MATERIALS AND METHODS Immunohistochemical studiesColonic tumour and paired normal mucosal tissue were obtained with agreement from the local ethical approval committee. Fivemicron thick, formalin-fixed tissue sections were cut and placed on coated glass slides. Sections were de-waxed and endogenous peroxidase activity quenched with 3% hydrogen peroxide. Sections were then incubated in donkey serum (Binding Site, Birmingham, UK) diluted 1/10 in PBS (15 min), followed by primary antibody diluted in PBS (1 hour). Antisera used were as follows: 17β-HSD2 monoclonal antiserum (1/500 dilution), a kind gift of Dr S Andersson (South Western Medical Center, Dallas, USA), was produced with a synthetic carboxyterminal peptide [C]RALRMP-NYKKKAT, corresponding to amino acids 375-387 in the human 17β-HSD2 protein; 17β-HSD4 monoclonal antibody (1:200 dilution), a kind gift of Dr J Adamski (GSF, Neuherberg, Germany) was prepared against the porcine 17β-HSD4 which cross-reacts with human, rat and mouse tissues. After washing, slides were incubated for 30 min with a biotinylated universal secondary antibody (Binding Site), diluted 1/100 in PBS, and binding visualised using ABC reagent (Binding Site) and 3,3′-diaminobenzidine (Sigma Chemical Co, Poole, UK). After staining, slides were washed and counterstained in Mayer's haematoxylin. Cell cultureColonic carcinoma cell lines (SW620, Caco-2 and HT-29) were routinely maintained in Dulbecco's Modified Eagles Medium (DMEM), supplemented wit...

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Section: Analysis Of 17β-hsd Activity In Vitrosupporting

confidence: 67%

mentioning

confidence: 99%

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

et al. 2000

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“…In line with this, English et al 28 reported that oxidative 17HSD activity was significantly lower in colon tumors compared to normal mucosa. Based on Northern analysis, they concluded that the decrease was due mainly to decreased expression of 17HSD type 4, another 17HSD enzyme with oxidative activity.…”

Section: Discussionmentioning

confidence: 62%

“…28,33 Enmark et al, 26 using in situ hybridization, showed that normal human colon cells express ER in the form of ER␤, which is markedly diminished in malignant colon tissues, 34 possibly through a posttranscriptional regulatory mechanism. In line with these results, our study showed that normal colon cells express ER␤ but not ER␣, while no ER subtype was detected in the malignant tissues.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Oduwole

Isomaa

Nokelainen

et al. 2001

Intl Journal of Cancer

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The 17HSDs are a group of isozymes that catalyze the interconversion between high-activity 17␤-hydroxysteroids and low-activity 17-ketosteroids. In the present study, we characterized the expression of 17HSD types 1 and 2 in normal and malignant gastrointestinal tissues and cells. Using the colon as a model for cancer of the gastrointestinal tract, expression of the 17HSD enzymes in cancer development was studied and correlated with proliferation and differentiation markers as assessed by Ki67 and mucin staining, respectively. In normal colon and small intestine, 17HSD type 2 mRNA was expressed in the surface epithelial cells and, to a lesser extent, in the cryptal epithelial cells. In colon-cancer specimens, 17HSD type 2 expression was downregulated both in the tissues and in the cell lines and correlated inversely with the proliferation marker. No expression for the 17HSD type 1 enzyme was observed in normal or cancerous gastrointestinal tract tissues. In line with the expression studies, 17HSD activity measurements with colon cells showed that only the oxidative conversion of E2 to E1 was present, and Northern blot analysis showed the signal only for 17HSD type 2. Localization of the ERs ␣ and ␤, assessed by immunohistochemistry and in situ hybridization, showed the presence of ER␤ in the lamina propria of the colon. Our study shows that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. The decrease in expression of the type 2 enzyme may increase estrogen influence in colon cancer. © 2002 Wiley-Liss, Inc. Key words: colon carcinoma; estrogen; hydroxysteroid dehydrogenase; cell proliferation; cell differentiationEpidemiologic studies 1,2 and in vitro studies with colon-cancer cell lines 3 suggest the involvement of estrogens in the development and progression of gastrointestinal cancer. [3][4][5] Contrary to this, however, is the indication that HRT is effective at reducing the incidence of colon cancer. 6 The mechanism underlying the sex steroid-mediated effects in normal gastrointestinal physiology and its involvement in neoplastic development and progression, if any, are far from clear.The 17HSDs play pivotal roles in the regulation of the physiologic activities of sex steroid hormones by catalyzing the oxidation or reduction of 17␤-hydroxy-and 17-ketosteroids, respectively. 7,8 17HSDs regulate the concentrations of the active sex steroids that bind to the respective steroid receptors to regulate gene expression in target cells. To date, at least 8 isoforms of the 17HSD enzyme with different substrate and cofactor specificities, tissue distributions and subcellular localizations have been characterized. 8,9 Of these isoforms, 17HSD type 1 and type 2 catalyze opposite reactions of estrogen metabolism. 17HSD type 1 is the predominant enzyme involved in estradiol biosynthesis (E1 to E2), and it is expressed in cells of placental and ovarian origin 10,11 as well as in breast tissue. 12 On the other hand, 17HSD type 2 catalyzes the oxidation of estrogens (E2 to E1...

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Deletion mapping of chromosome 16q24 in hepatocellular carcinoma in Taiwan and mutational analysis of the17-?-HSD gene localized to the region

Lin¹,

Lee²,

Chen³

et al. 2001

Int. J. Cancer

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Human chromosome band 16q24 commonly undergoes loss of heterozygosity (LOH) in human hepatocellular carcinoma (HCC). To further localize the region of deletion on 16q24 and to evaluate the genetic role of 17-beta-HSD, which is near 16q24, in HCC, we examined the pattern of loss of heterozygosity in 88 HCC patients. DNAs from 88 pairs of HCCs and corresponding non-tumor parts were prepared. Loss of heterozygosity on chromosomes 16q24 was investigated by 11 sets of microsatellite markers. Mutation analysis of type II 17-beta-HSD was performed by automatic sequencing. LOH on 16q24 for at least 1 locus was found in 43 of the 88 tumor DNAs (49%). Three non-overlapping regions of frequent LOH were defined in these 43 tumors with partial deletions. The first region was between D16S516 loci and D16S507, encompassed by a 1-cM region, defined by the D16S504. The second region was defined by the 17HSDB2 locus between D16S505 and D16S422, encompassed approximately by a 1-cM region. The third region was between D16S520 and D16S413, defined by D16S3048, encompassed approximately by a 4-cM region. Homozygous deletions of any exons in 17HSDB2 gene were identified in 7 of 27 cases (26%). Automated sequencing analysis of 17HSDB2 failed to demonstrate mutations in any of these specimens. Our data suggest that the 17HSDB2 locus is a frequent target of deletion in HCC but the inactivation of 17HSDB2 may not involve sequence mutations. Furthermore, the presence of the other 2 frequent LOH regions suggest that the putative tumor suppressor genes at these locations might be involved in the development of HCC. © 2001 Wiley-Liss, Inc. Hepatocellular carcinoma (HCC) is a malignancy with high incidence in Asia and South Africa. 1,2 In Taiwan, it ranks first in cancer mortality. The disease is known to be closely associated with chronic hepatitis B or C viral infection, 1,3 or exposer to aflatoxin B 1 and environmental factors. 1,4 The molecular mechanism of hepatocarcinogenesis, however, remains to be clarified.Recent studies have indicated that in HCC, frequent aberrations are present in several genomic regions, including 1p, 4q, 5q, 6q, 8p, 8q, 10q, 11p, 13q, 16q, 17p and 22q. 5-16 It has been suggested that accumulation of these genetic changes that affect the expression of oncogenes and tumor suppressor genes, occurred in a stepwise manner during the development and progression. Among these alterations, LOH on chromosome 16q has been reported to occur more frequently in HCCs of poor differentiation or larger size, and with metastasis. 16,17 Recently, in a comprehensive analysis of LOH and chromosomal abnormality in HCC, 12,18 we also identified frequent LOH on chromosome 16q, confirming that candidate tumor suppressor genes may be located on this chromosome.Deletion and rearrangement of chromosome 16q are also frequently seen in other cancers, including breast cancers, prostate carcinoma and Wilms' tumor. 17,19 -25 The commonly deleted regions in these tumors have been identified at 16q22.1 and 16q24 -qter. It is difficult, howev...

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Loss of Estrogen Inactivation in Colonic Cancer

Cited by 55 publications

References 27 publications

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Oestrogen inactivation in the colon: analysis of the expression and regulation of 17 β -hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer

Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

Deletion mapping of chromosome 16q24 in hepatocellular carcinoma in Taiwan and mutational analysis of the17-?-HSD gene localized to the region

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