Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.3 (HSD)
 3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sex steroids play a crucial role in the development and differentiation of normal mammary gland as well as in the regulation of breast cancer growth. Local intracrine formation of sex steroids from inactive precursors secreted by the adrenals, namely, dehydroepiandrosterone and its sulfate, may regulate growth and function of peripheral target tissues, including the breast. Both endocrine and paracrine influences on the proliferation of human breast cancer cells are well recognized. Breast tumors harbor tumor-associated macrophages and tumor-infiltrating lymphocytes that secrete a wide spectrum of cytokines. These factors may also contribute to neoplastic cell activity. The present study was designed to investigate the action of cytokines on 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity, which is an essential step in the biosynthesis of active estrogens and androgens in human breast cancer cell lines and in normal human mammary epithelial cells in primary culture. 3Beta-HSD activity was undetectable in ZR-75-1 and T-47D estrogen receptor-positive (ER)+ cells under basal growth conditions. This activity was markedly induced after exposure to picomolar concentrations of interleukin (IL)-4 or IL-13. The potent stimulatory effect of these cytokines on 3beta-HSD activity was also observed in the ER- MDA-MB-231 human breast cancer cell line and in normal human mammary epithelial cells (HMECs) in primary culture. The stimulation of 3beta-HSD activity by IL-4 and IL-13 results from a rapid increase in 3beta-HSD type 1 mRNA levels as measured by RT-PCR and Northern blot analyses. Such an induction of the 3beta-HSD activity may modulate androgenic and estrogenic biological responses as demonstrated using ZR-75-1 cells transfected with androgen- or estrogen-sensitive reporter constructs and treated with the adrenal steroid 5-androstene-3beta,17beta-diol. The DNA-binding activity of Stat6, a member of the signal transducers and activators of transcription gene family, is activated 30 min after exposure to IL-4 and IL-13 in human breast cancer cell lines as well as in HMECs in primary culture. In these cells, Stat6 activated by IL-4 or IL-13 binds to two regions of the 3beta-HSD type 1 gene promoter, containing Stat6 consensus sequences. IL-4 induction of 3beta-HSD mRNA and activity is sensitive to staurosporine. This protein kinase inhibitor also inhibits IL-4-induced Stat6 DNA-binding activity. Our data demonstrate for the first time that IL-4 and IL-13 induce 3beta-HSD type 1 gene expression, thus suggesting their involvement in the fine control of sex steroid biosynthesis from adrenal steroid precursors in normal and tumoral human mammary cells. Furthermore, aromatase and/or 5alpha-reductase(s) are expressed in the mammary gland and in a large proportion of human breast tumors. An increase in the formation of their substrates, namely, 4-androstenedione and testosterone, may well have a significant impact on the synthesis of active estrogens and androgens in these tissues.
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PMID:Induction of 3beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and interleukin-13. 989 13

The 3beta-hydroxysteroid dehydrogenase/isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. In humans there are two 3beta-HSD isoenzymes, the type 1 gene being predominantly expressed in the placenta and peripheral tissues, whereas the type 2 gene is the predominant 3beta-HSD expressed in the adrenal glands and gonads. We have recently showed that interleukin (IL)-4 and IL-13 induce 3beta-HSD type 1 gene expression in human breast cancer cell lines as well as in normal human mammary epithelial cells. The present study was designed to investigate whether such a cytokine-induced 3beta-HSD type 1 expression would also be observed in cell types derived from other peripheral sex steroid target tissues. To gain further knowledge about the molecular mechanism of IL-4 action, we have studied whether the induction of 3beta-HSD type 1 expression in IL-4-responsive cell types would always be associated with the activation of Stat6, a member of the Signal Transducers and Activators of Transcription (STAT) gene family. Stat6 is recognized as the principal transcription factor mediating the effects of IL-4. In normal human prostate epithelial cells (PrEC), no 3beta-HSD activity was detectable under basal culture conditions, while exposure to IL-4 or IL-13 caused a potent induction of this activity. This effect results from a rapid induction of 3beta-HSD type 1 messenger RNA levels as determined by Northern blot and RT-PCR analyses. Furthermore, IL-4 and IL-13 also increased 3beta-HSD type 1 gene expression in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, HT-29 colon cancer cells as well as in BT-20 and ZR-75-1 breast cancer cells. However, IL-4 and IL-13 failed to modulate the 3beta-HSD type 1 expression in human LnCAP and PC-3 prostate cancer cells, Caco-2 colon cancer cells as well as in JAR and JEG-3 choriocarcinoma cell lines. The DNA-binding activity of Stat6 was activated after a 30-min exposure to IL-4 in PrEC and in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid dehydroepiandrosterone, not only in breast cells but also in various cell types derived from peripheral target tissues, such as normal human prostate epithelial cells, immortalized keratinocytes, as well as colon and cervix cancer cell lines. Our data also demonstrates that the stimulatory effect of IL-4 was always associated with the activation of Stat6, thus supporting the essential role of Stat6 in this induction of 3beta-HSD type 1 gene expression.
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PMID:Induction of 3beta-hydroxysteroid dehydrogenase/isomerase type 1 expression by interleukin-4 in human normal prostate epithelial cells, immortalized keratinocytes, colon, and cervix cancer cell lines. 1049 13

There is evidence suggesting that local intracrine formation of sex steroids from inactive precursors, dehydroepiandrosterone (DHEA), its sulfate (DHEA-S) and 4-androstenedione (4-DIONE) plays an important role in the regulation of growth and function of peripheral target tissues. Moreover, human solid tumors are often infiltrated by stromal/immune cells secreting a wide spectra of cytokines. These cytokines might in turn regulate the activity of both immune and neoplastic cells. Our data demonstrate that the potent regulatory effects of interleukin-4 (IL-4) and IL-6 on both estrogenic and androgenic 17beta-HSD/KSR activities in breast cancer cells depend on the cell-specific gene expression of various types of 17beta-HSD/KSR enzymes. However, in both estrogen-receptor (ER)-positive (ZR-75-1, T-47D) and ER-negative (MDA-MB-231, BT-20) human breast cancer cells, exposure to IL-4 and IL-13 caused a rapid and potent induction of 3beta-HSD type 1 gene expression. Such an induction was also observed in normal human mammary and prostate epithelial cells in primary culture as well as in human HaCaT immortalized keratinocytes, ME-180 cervix cancer cells, and HT-29 colon cancer cells. The DNA-binding activity of Stat6, a member of the Signal Transducers and Activators of Transcription gene family, was activated after a 30 min exposure to IL-4 in all the cell types where IL-4 induced 3beta-HSD expression, but not in those that failed to respond to IL-4. Our data therefore suggest that IL-4 and IL-13 may play a role in the biosynthesis of active sex steroids from the inactive adrenal steroid DHEA, not only in breast cells but also in various cell types derived from peripheral target tissues.
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PMID:Crucial role of cytokines in sex steroid formation in normal and tumoral tissues. 1116 8

The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters.
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PMID:Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. 1138 80