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17β-Hydroxysteroid dehydrogenases—their role in pathophysiology
Molecular and Cellular Endocrinology 215 (2004) 83–88
17-Hydroxysteroid dehydrogenases—their role in pathophysiology P. Vihko∗ , P. Härkönen, P. Soronen, S. Törn, A. Herrala, R. Kurkela, A. Pulkka, O. Oduwole, V. Isomaa Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, P.O. Box 5000, FIN-90014, Oulu, Finland
Abstract 17-Hydroxysteroid dehydrogenases (17HSDs) regulate the biological activity of sex steroid hormones in a variety of tissues by catalyzing the interconversions between highly active steroid hormones, e.g. estradiol and testosterone, and corresponding less active hormones, estrone and androstenedione. Epidemiological and endocrine evidence indicates that estrogens play a role in the etiology of breast cancer, while androgens are involved in mechanisms controlling the growth of normal and malignant prostatic cells. Using LNCaP prostate cancer cell lines, we have developed a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition into more aggressive cells. Our data suggest that substantial changes in androgen and estrogen metabolism occur in the cells, leading to increased production of active estrogens during the process. In breast cancer, the reductive 17HSD type 1 activity is predominant in malignant cells, while the oxidative 17HSD type 2 mainly seems to be present in non-malignant breast epithelial cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach in treating estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered to be estrogen target tissues, such as the gastrointestinal tract. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Estrogen; Androgen; Breast cancer; Prostate cancer; Colon cancer
1. Introduction Female and male sex steroids, estrogens and androgens, are essential in reproduction, and there is increasing evidence that these hormones have general metabolic roles in a variety of peripheral tissues. The most potent female sex steroid is estradiol, its primary source in premenopausal women being the ovary, but circulating estrone and androgens originating from the adrenal gland are also converted into estradiol in peripheral tissues such as adipose tissue (Simpson et al., 1994). After menopause estrogen biosynthesis in peripheral tissues has a major role in estrogen action (Labrie, 1991). Testosterone is the main circulating androgen, and its 5␣-reduced metabolite dihydrotestosterone appears to be the main intracellular androgen in the prostate. Also in men, significant amounts of androgens are produced in target tissues (Labrie et al., 1997). In addition to their positive effects in both reproductive and non-reproductive organs, sex steroids are involved in the ∗ Corresponding author. Tel.: +358-40-5431734; fax: +358-8-3155631. E-mail address: [email protected] (P. Vihko).
development of hormone-dependent cancers, such as breast and prostate cancers. Estrogen and androgen-dependent tumors have been shown to contain steroid metabolizing enzymes including 17-hydroxysteroid dehydrogenases (17HSDs) that catalyze the interconversions between 17hydroxysteroids and 17-ketosteroids. Presently nine different 17HSD isoenzymes, types 1–5, 7–8, and 10–11 (Peltoketo et al., 1999, 2003; Adamski and Jakob, 2001) have been characterized in humans. Types 1, 3, 5, and 7 are reductive enzymes, whereas types 2, 4, 8, 10, and 11 are oxidative enzymes.
2. Enzymatic characteristics and function of 17HSD types 1, 2, 5, and 7 Human 17HSD types 1 and 2 belong to the short-chain dehydrogenase/reductase (SDR) protein family, but differ from each other in many respects. The main difference between the enzymes is the direction of their enzymatic activities. Human 17HSD type 1 mainly catalyzes reduction of estrone to estradiol (Puranen et al., 1997), preferring the phosphorylated form of nicotinamide-adenine dinucleotide,
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NADPH, as a cofactor. In cultured cells, the human type 1 enzyme is also capable of reducing androstenedione and 5␣-androstanedione to some extent, but it clearly gives preference to phenolic substrates over androgens. 17HSD type 2 predominantly catalyzes opposite reactions, converting estradiol to estrone, testosterone to androstenedione and 5␣-dihydrotestosterone to 5␣-androstanedione (Wu et al., 1993; Puranen et al., 1999), and it acts most efficiently in the presence of the non-phosphorylated form of the cofactor NAD+ (Labrie et al., 1997). 17HSD type 1 is an essential part of the estradiol production machinery, and it is most abundantly expressed in the granulosa cells of the ovary (Ghersevich et al., 1994; Sawetawan et al., 1994) and syncytiotrophoblasts of the placenta (Fournet-Dulguerov et al., 1987; Mäentausta et al., 1990), which secrete estradiol into the circulation. In addition, the type 1 enzyme contributes to the estrogen response by converting estrone to estradiol locally in certain targets of estrogen action, such as breast tissue (Poutanen et al., 1995; Sasano et al., 1996). 17HSD type 2 is involved in the inactivation and excretion of estradiol and testosterone. The type 2 enzyme may restrict the access of the active sex steroids into the circulation, and it may protect target tissues of hormone action against excessive sex hormone influence by catalyzing the conversion of androgens and estrogens into less active forms. 17HSD type 2 is expressed in a wide variety of tissues, such as breast, uterus, prostate, placenta, liver and kidney (Peltoketo et al., 1999, 2003). Typically, the type 2 enzyme is expressed in epithelial cells, such as the surface epithelial cells of the gastrointestinal tract (Mustonen et al., 1998a). In the placenta, the type 2 enzyme may limit the access of fetal androgens to maternal tissue and the access of maternal estrogen into the fetus, acting as a barrier between the fetus and mother (Mustonen et al., 1998b). 17HSD type 5, a reductive 17HSD, is a member of aldo-keto reductase superfamily (Deyashiki et al., 1995). The enzyme is expressed in the liver, prostate, endometrium, mammary gland and ovary (Luu-The et al., 2001; Penning et al., 2001). Recent studies have shown that the enzyme is the suppressor of nuclear receptor-regulated cell differentiation, and that progesterone and prostaglandin D2 are the key substrates of 17HSD type 5 (Luu-The et al., 2001; Desmond et al., 2003). In addition, 17HSD type 5 has to some extent activity as a reductase of 3-keto and 17-keto and as an oxidase of 3␣-hydroxysteroids and 17-hydroxysteroids (Penning et al., 2001). Human 17HSD type 7 is a membrane-associated reductive enzyme converting estrone to estradiol and 5␣-dihydrotestosterone to an estrogenic metabolite, 5␣-androstane-3, 17-diol, thereby catalyzing the reduction of the keto group in either 17- or 3-position of the substrate. Minor 3HSD-like activity towards progesterone and 20-hydroxyprogesterone, leading to inactivation of progesterone by 17HSD type 7, was also detected (Törn et al., 2003). Human 17HSD type 7 is expressed in steroidogenic and several pe-
ripheral tissues such as liver, lung and thymus. Its function is not known, but it may be responsible for the local production of estrogenic metabolites in peripheral tissue (Törn et al., 2003). 17HSD type 7 may also have other substrates besides sex steroids (Breitling et al., 2001).
3. 17HSDs in the prostate Androgen action is regulated locally in the prostate by several steroid metabolizing enzymes, such as 5␣-reductases, which convert the major circulating androgen testosterone into the major prostatic androgen 5␣-dihydrotestosterone (Labrie et al., 1997). Our previous data have shown that of the 17HSD enzymes the type 2 enzyme is expressed in benign and malignant human prostate, and higher expression of 17HSD type 2 has been detected in benign prostatic hyperplasia compared with prostatic carcinoma (Elo et al., 1996). In cultured cells the enzyme converts 5␣-dihydrotestosterone and testosterone into their corresponding 17-keto derivatives. It was therefore suggested that the amount of active androgens in prostatic epithelial cells can be decreased by the local action of 17HSD type 2, and that the type 2 enzyme can thus protect prostatic cells from excessive androgen influence. Intraprostatic concentrations of active androgens also maintain organ homeostasis by regulating the balance between proliferation and apoptotic cell death of prostatic epithelial cells. Decreased local inactivation of androgens in the prostate could, therefore, shift the balance towards cell proliferation. Using LNCaP prostate cancer cells, we have developed a model to study mechanisms involved in the transition of prostate cancer to an androgen-independent stage (Härkönen et al., 2003). During the culture the net-forming LnCaP-cells in close contact with each other are transformed into the more aggressive, androgen-independent small round-shaped cells that have lost their contacts and are able to grow in the suspension culture. Concomitantly with the development of the androgen-independent stage, LNCaP cells lost their ability to produce detectable amounts of prostate specific antigen (Härkönen et al., 2003). In cultures without androgens, the cells are transformed into small round-shaped cells via neuroendocrine cells (Fig. 1). To get insight into changes in steroid metabolism during the cellular transformation, the conversion of several estrogenic and androgenic substrates into their specific products was investigated. The data indicate that non-transformed LNCaP cells possess predominant oxidative 17HSD activity converting estradiol, testosterone and dihydrotestosterone into their less active 17-keto derivatives estrone, androstenedione and 5␣-androstanedione, respectively. At the transformed stage, the oxidative activity was dramatically decreased and the LNCaP cells possessed remarkable reductive activity. To get more information on the potential enzymes responsible for the oxidative and reductive
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4. 17HSDs in breast epithelial cells
Fig. 1. Light microscopy of morphological changes of LNCaP cells during the transformation. (A) Untransformed cells; (B) neuroendocrine cells; and (C) transformed cells.
activities, the expression levels of candidate genes, 17HSD types 2, 5, and 7, were determined. During the cellular transformation the relative expression of HSD17B2 gene decreased strongly. At the same time there was an increase in the expression of genes encoding 17HSD types 5 and 7 (Härkönen et al., 2003). The observation of a remarkable decrease in oxidative 17HSD type 2 activity during cellular transformation is in line with our previous studies. We have identified in prostate cancer specimens at least three independent deleted regions at 16q, the most common being 16q24.1–16q24.2, which includes the gene for 17HSD type 2. The data further suggested an association between allelic loss at 16q24.1–16q24.2 and the clinically aggressive features of prostatic cancer (Elo et al., 1997, 1999).
Both 17HSD types 1 and 2 are expressed in normal breast tissue of premenopausal women (Söderqvist et al., 1998; Miettinen et al., 1999). Expression of the type 1 enzyme takes place in ductal or lobular epithelial cells throughout the menstrual cycle, correlating with the presence of estrogen receptor. The presence of 17HSD type 2 mRNA in normal breast epithelial cells has been shown using in situ hybridization. 17HSD types 1 and 2 mRNAs have also been detected in human mammary epithelial cell lines (Miettinen et al., 1999) and primary cultures (Speirs et al., 1999) derived from women undergoing reduction mammoplasty. Oxidative 17HSD activity leading to the conversion of estradiol to estrone has been detected to be up to 50 times more predominant over reductive 17HSD activity in these cells. Expression of both 17HSD types 1 and 2 also takes place in malignant breast cells. About 50% of malignant breast specimens show positive immunohistochemical staining for 17HSD type 1 (Poutanen et al., 1992; Sasano et al., 1996). The breast cancer cell lines analyzed (Miettinen et al., 1996a) have been found to express 17HSD type 1, 17HSD type 2, or both enzymes. In malignant breast cells the reductive activity is dominant over oxidative 17HSD activity (Speirs et al., 1998). Accumulation of estradiol in cancer tissue has been detected in postmenopausal women (Vermeulen et al., 1986) and may result from higher aromatase, steroid sulfatase and reductive 17HSD activity. A recent study showed that the estradiol/estrone ratio and expression of 17HSD type 1, but not that of aromatase or sulfatase is higher in breast cancer tissues of postmenopausal compared to premenopausal patients (Miyoshi et al., 2001). This suggests that 17HSD type 1 is mainly responsible for intracellular accumulation of estradiol in malignant breast epithelial cells. Moreover, in the presence of 17HSD type 1, administration of estrone results in similar growth of breast cancer cells which estradiol causes alone, while estrone does not have the same effect in control cells without 17HSD type 1 (Miettinen et al., 1996b). Altogether, the data suggest that local biosynthesis has an impact on the estrogen response. A predominance of 17HSD type 1 in malignant breast tissue may lead to increased estrogen-dependent proliferation and progress of cancer.
5. 17HSD type 2 in intestinal cancers Epidemiological studies and in vitro cell line studies with colon cancer cell lines have suggested the involvement of estrogens in the development and progression of gastrointestinal cancers. Additional information on the physiological importance of steroid metabolism in the intestine has been obtained by localizing 17HSD type 2 in mouse tissues. The data showed that the enzyme is expressed in several epithelial layers of the gastrointestinal and urogenital tracts
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line with these results, English et al. reported that oxidative 17HSD activity was significantly lower in colon tumors as compared to normal mucosa (English et al., 1999). Based on Northern analysis, they concluded that the decrease was due mainly to decreased expression of 17HSD type 4, another 17HSD type with oxidative activity. In another report, the same authors show that expressions of both 17HSD types 2 and 4 are decreased in colon tumors (English et al., 2000). All the data suggest that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. In summary, local regulation of the concentrations of active androgens and estrogens is important for the maintenance of organ homeostasis. In the prostate, estrogens together with androgens may be involved in the abnormal growth of the tissue, even though the precise roles of the hormones remain undefined. A predominance of 17HSD type 1 in malignant breast tissue may lead to increased estrogen-dependent proliferation and cancer progression, while oxidative 17HSD type 2 may protect normal breast cells from an estradiol effect. In the intestinal tract, high expression of the 17HSD type 2 enzyme is a pervasive feature of surface epithelium, and development of colon cancer is associated with a decrease of 17HSD type 2 expression.
Fig. 2. Light microscopic images of normal colon (A) and gastric mucosa (C) showing expression of 17HSD type 2 mRNA in the epithelial cells. Sense probe showed no signal (B) and (D). Bars (A) and (B) 10 m; (C) and (D) 20 m.
(Mustonen et al., 1998a). The localization and intensity of 17HSD type 2 mRNA expression was, furthermore, identical in the gastrointestinal tracts of both male and female mice. During embryogenesis its expression strongly increased in parallel with the fetal development of gastrointestinal organs (Mustonen et al., 1997). All these data suggest a role for 17HSD type 2 in the inactivation of sex steroids and steroid-like compounds present in the intestinal contents. We analyzed the expression of human 17HSD types 1 and 2 in normal gastric tissue, small intestine and colon as well as in gastric and colon cancer in both females and males using in situ hybridization. No expression of 17HSD type 1 was observed in normal and cancerous gastrointestinal tract tissues (Oduwole et al., 2002, 2003). In normal gastric mucosa, 17HSD type 2 was observed in well-differentiated cells of the surface epithelium and the villous epithelium (Fig. 2). Intestinal metaplasia showed up-regulation of 17HSD type 2, and significant down-regulation was evident in intestinal cancer (Oduwole et al., 2003). 17HSD type 2 mRNA was highly expressed in the surface epithelium of normal colon (Fig. 2) and small intestine of both female and male patients, and it was down-regulated in colon cancer tissues and cell lines (Oduwole et al., 2002). The down-regulation was already evident in adenoma, suggesting that the decrease in the expression is an early process in colon carcinogenesis. In
Acknowledgements This work was supported by the Research Council for Health of the Academy of Finland (Project Nos. 47630 and 51618), the Finnish Cancer Foundation and the Sigrid Juselius Foundation.
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17-Hydroxysteroid dehydrogenases—their role in pathophysiology P. Vihko∗ , P. Härkönen, P. Soronen, S. Törn, A. Herrala, R. Kurkela, A. Pulkka, O. Oduwole, V. Isomaa Biocenter Oulu and Research Center for Molecular Endocrinology, University of Oulu, P.O. Box 5000, FIN-90014, Oulu, Finland
Abstract 17-Hydroxysteroid dehydrogenases (17HSDs) regulate the biological activity of sex steroid hormones in a variety of tissues by catalyzing the interconversions between highly active steroid hormones, e.g. estradiol and testosterone, and corresponding less active hormones, estrone and androstenedione. Epidemiological and endocrine evidence indicates that estrogens play a role in the etiology of breast cancer, while androgens are involved in mechanisms controlling the growth of normal and malignant prostatic cells. Using LNCaP prostate cancer cell lines, we have developed a cell model to study the progression of prostate cancer. In the model LNCaP cells are transformed in culture condition into more aggressive cells. Our data suggest that substantial changes in androgen and estrogen metabolism occur in the cells, leading to increased production of active estrogens during the process. In breast cancer, the reductive 17HSD type 1 activity is predominant in malignant cells, while the oxidative 17HSD type 2 mainly seems to be present in non-malignant breast epithelial cells. Deprivation of an estrogen response by using specific 17HSD type 1 inhibitors is a tempting approach in treating estrogen-dependent breast cancer. Our recent studies demonstrate that in addition to sex hormone target tissues, estrogens may be important in the development of cancer in some other tissues previously not considered to be estrogen target tissues, such as the gastrointestinal tract. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Estrogen; Androgen; Breast cancer; Prostate cancer; Colon cancer
1. Introduction Female and male sex steroids, estrogens and androgens, are essential in reproduction, and there is increasing evidence that these hormones have general metabolic roles in a variety of peripheral tissues. The most potent female sex steroid is estradiol, its primary source in premenopausal women being the ovary, but circulating estrone and androgens originating from the adrenal gland are also converted into estradiol in peripheral tissues such as adipose tissue (Simpson et al., 1994). After menopause estrogen biosynthesis in peripheral tissues has a major role in estrogen action (Labrie, 1991). Testosterone is the main circulating androgen, and its 5␣-reduced metabolite dihydrotestosterone appears to be the main intracellular androgen in the prostate. Also in men, significant amounts of androgens are produced in target tissues (Labrie et al., 1997). In addition to their positive effects in both reproductive and non-reproductive organs, sex steroids are involved in the ∗ Corresponding author. Tel.: +358-40-5431734; fax: +358-8-3155631. E-mail address: [email protected] (P. Vihko).
development of hormone-dependent cancers, such as breast and prostate cancers. Estrogen and androgen-dependent tumors have been shown to contain steroid metabolizing enzymes including 17-hydroxysteroid dehydrogenases (17HSDs) that catalyze the interconversions between 17hydroxysteroids and 17-ketosteroids. Presently nine different 17HSD isoenzymes, types 1–5, 7–8, and 10–11 (Peltoketo et al., 1999, 2003; Adamski and Jakob, 2001) have been characterized in humans. Types 1, 3, 5, and 7 are reductive enzymes, whereas types 2, 4, 8, 10, and 11 are oxidative enzymes.
2. Enzymatic characteristics and function of 17HSD types 1, 2, 5, and 7 Human 17HSD types 1 and 2 belong to the short-chain dehydrogenase/reductase (SDR) protein family, but differ from each other in many respects. The main difference between the enzymes is the direction of their enzymatic activities. Human 17HSD type 1 mainly catalyzes reduction of estrone to estradiol (Puranen et al., 1997), preferring the phosphorylated form of nicotinamide-adenine dinucleotide,
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NADPH, as a cofactor. In cultured cells, the human type 1 enzyme is also capable of reducing androstenedione and 5␣-androstanedione to some extent, but it clearly gives preference to phenolic substrates over androgens. 17HSD type 2 predominantly catalyzes opposite reactions, converting estradiol to estrone, testosterone to androstenedione and 5␣-dihydrotestosterone to 5␣-androstanedione (Wu et al., 1993; Puranen et al., 1999), and it acts most efficiently in the presence of the non-phosphorylated form of the cofactor NAD+ (Labrie et al., 1997). 17HSD type 1 is an essential part of the estradiol production machinery, and it is most abundantly expressed in the granulosa cells of the ovary (Ghersevich et al., 1994; Sawetawan et al., 1994) and syncytiotrophoblasts of the placenta (Fournet-Dulguerov et al., 1987; Mäentausta et al., 1990), which secrete estradiol into the circulation. In addition, the type 1 enzyme contributes to the estrogen response by converting estrone to estradiol locally in certain targets of estrogen action, such as breast tissue (Poutanen et al., 1995; Sasano et al., 1996). 17HSD type 2 is involved in the inactivation and excretion of estradiol and testosterone. The type 2 enzyme may restrict the access of the active sex steroids into the circulation, and it may protect target tissues of hormone action against excessive sex hormone influence by catalyzing the conversion of androgens and estrogens into less active forms. 17HSD type 2 is expressed in a wide variety of tissues, such as breast, uterus, prostate, placenta, liver and kidney (Peltoketo et al., 1999, 2003). Typically, the type 2 enzyme is expressed in epithelial cells, such as the surface epithelial cells of the gastrointestinal tract (Mustonen et al., 1998a). In the placenta, the type 2 enzyme may limit the access of fetal androgens to maternal tissue and the access of maternal estrogen into the fetus, acting as a barrier between the fetus and mother (Mustonen et al., 1998b). 17HSD type 5, a reductive 17HSD, is a member of aldo-keto reductase superfamily (Deyashiki et al., 1995). The enzyme is expressed in the liver, prostate, endometrium, mammary gland and ovary (Luu-The et al., 2001; Penning et al., 2001). Recent studies have shown that the enzyme is the suppressor of nuclear receptor-regulated cell differentiation, and that progesterone and prostaglandin D2 are the key substrates of 17HSD type 5 (Luu-The et al., 2001; Desmond et al., 2003). In addition, 17HSD type 5 has to some extent activity as a reductase of 3-keto and 17-keto and as an oxidase of 3␣-hydroxysteroids and 17-hydroxysteroids (Penning et al., 2001). Human 17HSD type 7 is a membrane-associated reductive enzyme converting estrone to estradiol and 5␣-dihydrotestosterone to an estrogenic metabolite, 5␣-androstane-3, 17-diol, thereby catalyzing the reduction of the keto group in either 17- or 3-position of the substrate. Minor 3HSD-like activity towards progesterone and 20-hydroxyprogesterone, leading to inactivation of progesterone by 17HSD type 7, was also detected (Törn et al., 2003). Human 17HSD type 7 is expressed in steroidogenic and several pe-
ripheral tissues such as liver, lung and thymus. Its function is not known, but it may be responsible for the local production of estrogenic metabolites in peripheral tissue (Törn et al., 2003). 17HSD type 7 may also have other substrates besides sex steroids (Breitling et al., 2001).
3. 17HSDs in the prostate Androgen action is regulated locally in the prostate by several steroid metabolizing enzymes, such as 5␣-reductases, which convert the major circulating androgen testosterone into the major prostatic androgen 5␣-dihydrotestosterone (Labrie et al., 1997). Our previous data have shown that of the 17HSD enzymes the type 2 enzyme is expressed in benign and malignant human prostate, and higher expression of 17HSD type 2 has been detected in benign prostatic hyperplasia compared with prostatic carcinoma (Elo et al., 1996). In cultured cells the enzyme converts 5␣-dihydrotestosterone and testosterone into their corresponding 17-keto derivatives. It was therefore suggested that the amount of active androgens in prostatic epithelial cells can be decreased by the local action of 17HSD type 2, and that the type 2 enzyme can thus protect prostatic cells from excessive androgen influence. Intraprostatic concentrations of active androgens also maintain organ homeostasis by regulating the balance between proliferation and apoptotic cell death of prostatic epithelial cells. Decreased local inactivation of androgens in the prostate could, therefore, shift the balance towards cell proliferation. Using LNCaP prostate cancer cells, we have developed a model to study mechanisms involved in the transition of prostate cancer to an androgen-independent stage (Härkönen et al., 2003). During the culture the net-forming LnCaP-cells in close contact with each other are transformed into the more aggressive, androgen-independent small round-shaped cells that have lost their contacts and are able to grow in the suspension culture. Concomitantly with the development of the androgen-independent stage, LNCaP cells lost their ability to produce detectable amounts of prostate specific antigen (Härkönen et al., 2003). In cultures without androgens, the cells are transformed into small round-shaped cells via neuroendocrine cells (Fig. 1). To get insight into changes in steroid metabolism during the cellular transformation, the conversion of several estrogenic and androgenic substrates into their specific products was investigated. The data indicate that non-transformed LNCaP cells possess predominant oxidative 17HSD activity converting estradiol, testosterone and dihydrotestosterone into their less active 17-keto derivatives estrone, androstenedione and 5␣-androstanedione, respectively. At the transformed stage, the oxidative activity was dramatically decreased and the LNCaP cells possessed remarkable reductive activity. To get more information on the potential enzymes responsible for the oxidative and reductive
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4. 17HSDs in breast epithelial cells
Fig. 1. Light microscopy of morphological changes of LNCaP cells during the transformation. (A) Untransformed cells; (B) neuroendocrine cells; and (C) transformed cells.
activities, the expression levels of candidate genes, 17HSD types 2, 5, and 7, were determined. During the cellular transformation the relative expression of HSD17B2 gene decreased strongly. At the same time there was an increase in the expression of genes encoding 17HSD types 5 and 7 (Härkönen et al., 2003). The observation of a remarkable decrease in oxidative 17HSD type 2 activity during cellular transformation is in line with our previous studies. We have identified in prostate cancer specimens at least three independent deleted regions at 16q, the most common being 16q24.1–16q24.2, which includes the gene for 17HSD type 2. The data further suggested an association between allelic loss at 16q24.1–16q24.2 and the clinically aggressive features of prostatic cancer (Elo et al., 1997, 1999).
Both 17HSD types 1 and 2 are expressed in normal breast tissue of premenopausal women (Söderqvist et al., 1998; Miettinen et al., 1999). Expression of the type 1 enzyme takes place in ductal or lobular epithelial cells throughout the menstrual cycle, correlating with the presence of estrogen receptor. The presence of 17HSD type 2 mRNA in normal breast epithelial cells has been shown using in situ hybridization. 17HSD types 1 and 2 mRNAs have also been detected in human mammary epithelial cell lines (Miettinen et al., 1999) and primary cultures (Speirs et al., 1999) derived from women undergoing reduction mammoplasty. Oxidative 17HSD activity leading to the conversion of estradiol to estrone has been detected to be up to 50 times more predominant over reductive 17HSD activity in these cells. Expression of both 17HSD types 1 and 2 also takes place in malignant breast cells. About 50% of malignant breast specimens show positive immunohistochemical staining for 17HSD type 1 (Poutanen et al., 1992; Sasano et al., 1996). The breast cancer cell lines analyzed (Miettinen et al., 1996a) have been found to express 17HSD type 1, 17HSD type 2, or both enzymes. In malignant breast cells the reductive activity is dominant over oxidative 17HSD activity (Speirs et al., 1998). Accumulation of estradiol in cancer tissue has been detected in postmenopausal women (Vermeulen et al., 1986) and may result from higher aromatase, steroid sulfatase and reductive 17HSD activity. A recent study showed that the estradiol/estrone ratio and expression of 17HSD type 1, but not that of aromatase or sulfatase is higher in breast cancer tissues of postmenopausal compared to premenopausal patients (Miyoshi et al., 2001). This suggests that 17HSD type 1 is mainly responsible for intracellular accumulation of estradiol in malignant breast epithelial cells. Moreover, in the presence of 17HSD type 1, administration of estrone results in similar growth of breast cancer cells which estradiol causes alone, while estrone does not have the same effect in control cells without 17HSD type 1 (Miettinen et al., 1996b). Altogether, the data suggest that local biosynthesis has an impact on the estrogen response. A predominance of 17HSD type 1 in malignant breast tissue may lead to increased estrogen-dependent proliferation and progress of cancer.
5. 17HSD type 2 in intestinal cancers Epidemiological studies and in vitro cell line studies with colon cancer cell lines have suggested the involvement of estrogens in the development and progression of gastrointestinal cancers. Additional information on the physiological importance of steroid metabolism in the intestine has been obtained by localizing 17HSD type 2 in mouse tissues. The data showed that the enzyme is expressed in several epithelial layers of the gastrointestinal and urogenital tracts
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line with these results, English et al. reported that oxidative 17HSD activity was significantly lower in colon tumors as compared to normal mucosa (English et al., 1999). Based on Northern analysis, they concluded that the decrease was due mainly to decreased expression of 17HSD type 4, another 17HSD type with oxidative activity. In another report, the same authors show that expressions of both 17HSD types 2 and 4 are decreased in colon tumors (English et al., 2000). All the data suggest that 17HSD type 2 expression is associated with the functional integrity of the gastrointestinal tract. In summary, local regulation of the concentrations of active androgens and estrogens is important for the maintenance of organ homeostasis. In the prostate, estrogens together with androgens may be involved in the abnormal growth of the tissue, even though the precise roles of the hormones remain undefined. A predominance of 17HSD type 1 in malignant breast tissue may lead to increased estrogen-dependent proliferation and cancer progression, while oxidative 17HSD type 2 may protect normal breast cells from an estradiol effect. In the intestinal tract, high expression of the 17HSD type 2 enzyme is a pervasive feature of surface epithelium, and development of colon cancer is associated with a decrease of 17HSD type 2 expression.
Fig. 2. Light microscopic images of normal colon (A) and gastric mucosa (C) showing expression of 17HSD type 2 mRNA in the epithelial cells. Sense probe showed no signal (B) and (D). Bars (A) and (B) 10 m; (C) and (D) 20 m.
(Mustonen et al., 1998a). The localization and intensity of 17HSD type 2 mRNA expression was, furthermore, identical in the gastrointestinal tracts of both male and female mice. During embryogenesis its expression strongly increased in parallel with the fetal development of gastrointestinal organs (Mustonen et al., 1997). All these data suggest a role for 17HSD type 2 in the inactivation of sex steroids and steroid-like compounds present in the intestinal contents. We analyzed the expression of human 17HSD types 1 and 2 in normal gastric tissue, small intestine and colon as well as in gastric and colon cancer in both females and males using in situ hybridization. No expression of 17HSD type 1 was observed in normal and cancerous gastrointestinal tract tissues (Oduwole et al., 2002, 2003). In normal gastric mucosa, 17HSD type 2 was observed in well-differentiated cells of the surface epithelium and the villous epithelium (Fig. 2). Intestinal metaplasia showed up-regulation of 17HSD type 2, and significant down-regulation was evident in intestinal cancer (Oduwole et al., 2003). 17HSD type 2 mRNA was highly expressed in the surface epithelium of normal colon (Fig. 2) and small intestine of both female and male patients, and it was down-regulated in colon cancer tissues and cell lines (Oduwole et al., 2002). The down-regulation was already evident in adenoma, suggesting that the decrease in the expression is an early process in colon carcinogenesis. In
Acknowledgements This work was supported by the Research Council for Health of the Academy of Finland (Project Nos. 47630 and 51618), the Finnish Cancer Foundation and the Sigrid Juselius Foundation.
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