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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intratumoral expression of aromatase P450 (P450arom) promotes the growth of breast tumors via increased local estrogen concentration. We cloned a novel 101-bp untranslated first exon (I.7) that comprises the 5'-end of 29-54% of P450arom transcripts isolated from breast cancer tissues (n = 7). The levels of P450arom transcripts with exon I.7 were significantly increased in breast tumor tissues and adipose tissue adjacent to tumors. We identified a promoter immediately upstream of exon I.7 and mapped this to about 36 kb upstream of ATG translation start site of the CYP19 (aromatase cytochrome P450) gene. Sequence analysis of I.7 revealed a TATA-less promoter containing an initiator, two consensus GATA sites, and cis-regulatory elements found in megakaryocytes and endothelial type promoters. Luciferase activity directed by the promoter I.7 sequence (-299/+81 bp) was 4-fold greater than a minimum length promoter sequence (-35/+81 bp) in human microvascular endothelial cells (HMEC-1), but only 2-fold greater in MCF-7 breast malignant epithelial cells. There was no promoter activity in primary breast adipose fibroblasts. Site-directed mutations demonstrated that maximal basal promoter activity required two GATA motifs at -146/-141 bp and -196/-191 bp. Gel shift and deoxyribonuclease I footprinting assays demonstrated the binding of GATA-2 transcription factor but not GATA-1 to the -196/-191-bp region. Overexpression of GATA-2 in HMEC-1 cells increases promoter I.7 activity by 5-fold. In conclusion, promoter I.7 is a GATA-2-regulated endothelial promoter of the human CYP19 gene and may increase estrogen biosynthesis in vascular endothelial cells of breast cancer. The activity of this promoter may also be important for intracrine and paracrine effects of estrogen on blood vessels.
Mol Endocrinol 2002 Oct
PMID:Cloning and characterization of a novel endothelial promoter of the human CYP19 (aromatase P450) gene that is up-regulated in breast cancer tissue. 1235 90

This work describes the molecular cloning of the cDNA encoding the rainbow trout (Oncorhynchus mykiss Walbaum) brain cytochrome P450arom by means of reverse transcriptase and polymerase chain reaction (RT-PCR) and 5'- and 3'-rapid amplification of cDNA ends (RACE) analyses. The results obtained demonstrate that, as in other teleost fishes, the trout genome contains, besides the gene previously identified in the ovary, a second CYP19 gene (CYP19B) expressed at high level in the brain. Moreover, two P450aromB mRNAs, forms I and II, were found to be transcribed in trout. Form I (1816 sequenced nt) contains an open reading frame (ORF) of 1464b, a 5'-untranslated terminal region (UTR) of 124b and at least 228b in the 3'-UTR (incomplete, as the polyadenylation signal was not determined). Form II (1930 sequenced nt) contains an ORF of 1362b, a 5'-UTR of 340b and the same 3'-UTR as form I. Form II lacks the first 34 amino acids of form I, corresponding to the membrane-anchoring segment, whereas the sequence of the remaining coding region is almost the same in the two forms, resulting in proteins of 454 and 488 amino acids, respectively. Whether the two transcripts derive from the same gene by alternative splicing or are encoded by different CYP19B genes remains to be clarified. On Northern blot analyses with brain and ovary specific ORF probes and poly(A)(+)-enriched RNAs from trout ovary and brain, a transcript of about 2.6kb was identified in the ovary, as expected, whereas the full-length mRNA of brain P450arom is about 3.8kb. The brain form is expressed in the brain and gonads, whereas expression in peripheral tissues is limited mostly to the gills. The two trout CYP19 genes are not equivalent in tissue-specific expression, indicating the possibility of distinct promoters and regulatory mechanisms.
J Steroid Biochem Mol Biol 2002 Sep
PMID:Cloning of two mRNA variants of brain aromatase cytochrome P450 in rainbow trout (Oncorhynchus mykiss Walbaum). 1242 36

Breast cancer is the most prevalent cancer among women in Western countries, and its prevalence is also increasing in Asia. The major risk factor for breast cancer can be traced to reproductive events that influence the lifetime levels of hormones. However, a large percentage of breast cancer cases cannot, be explained by these risk factors. The identification of susceptibility factors that predispose individuals to breast cancer (for instance, if they are exposed to particular environmental agents) could possibly give further insight into the etiology of this malignancy and provide targets for the future development of therapeutics. The most interesting candidate genes include those that mediate a range of functions. These include carcinogen metabolism, DNA repair, steroid hormone metabolism, signal transduction, and cell cycle control. we conducted a hospital-based case-control study on South Korea to evaluate the potential modifying role of the genetic pollymprphisms of selected low penetrance gens that are involved carcinogen metabolisms (i.e., CYP1A1, CYP2E1, GSTM1/T1/P1, NAT1/2, etc.), estrogen synthesis and metabolism (i.e., CYP19, CYP17, CYP1B1, COMT, ER-alpha, etc.), DNA repair (i.e., XRCC1/3, ERCC2/4, ATM, AGT, etc.), and signal transduction as well as others (i.e., TGF- beta, IGF-1, TNF- beta, IL-1B, IL-1RN, etc.). We also took into account the potential interaction between these and the known risk factors of breast cancer. The results of selected genes will be presented in this mini-review.
J Biochem Mol Biol 2003 Jan 31
PMID:Genetic polymorphisms and cancer susceptibility of breast cancer in Korean women. 1254 72

Aromatase, the product of the CYP19 gene, plays a key role in androgenic steroids transformation into estrogens from various hormonal sensitive tissues. Thus, in situ expression of CYP19 has been suggested to be involved in breast tumor growth especially in post-menopausal patients.We developed a real-time quantitative RT-PCR assay based on fluorescent TaqMan methodology to quantify total CYP19 gene expression at the mRNA level in breast tumors. This method, based on nucleic acid quantification in homogeneous solutions, has the potential to become a standard in terms of its sensitivity, wide dynamic range and high-throughput capacity. In a well-defined series of 107 post-menopausal breast tumor samples, relative CYP19 mRNA levels ranged from 1 to 131. Among the four major CYP19 exon I-spliced transcripts, designated I.a, I.b, I.c and I.d, mRNA levels of the latter three correlated positively with total CYP19 mRNA levels. In ER alpha-positive breast tumors, CYP19 and ER alpha mRNA levels correlated negatively with each other (P=0.0078, r=-0.266), while CYP19 and ER beta mRNA levels correlated positively (P=0.00012, r=+0.388). Patients with high CYP19 mRNA levels did not relapse more frequently or have shorter relapse-free survival than other patients. Finally, mRNA levels of IL6, a major CYP19 regulatory factor, were significantly higher in tumors strongly expressing CYP19 than in tumors weakly expressing CYP19 (P=0.018). In conclusion, CYP19 expression did not influence the outcome of post-menopausal patients with breast cancer.
J Steroid Biochem Mol Biol 2002 Nov
PMID:Real-time reverse transcription PCR assay of CYP19 expression: application to a well-defined series of post-menopausal breast carcinomas. 1258 39

Aromatase (CYP19) is the estrogen synthetase that converts androgen to estrogen. The expression of aromatase in breast cancer cells and surrounding stromal cells is up regulated compared to non-cancerous cells. In situ estrogen synthesis is thought to stimulate breast cancer growth in both an autocrine and a paracrine manner. A complex mechanism is involved in the control of human aromatase expression, in that seven promoters have been identified and found to be utilized in a tissue-selective manner. Increased aromatase expression in breast tumors is, in part, attributed to changes in the transcriptional control of aromatase expression. While promoter I.4 is the main promoter that controls aromatase expression in non-cancer breast tissue, promoters II and I.3 are the dominant promoters that drive aromatase expression in breast cancer tissue. During the last several years, our laboratory performed a series of studies to examine the transcription regulatory mechanism of aromatase expression in breast cancer cells. We functionally characterized promoters II and I.3, and carried out DNase 1 footprinting analysis that identified two regulatory elements, S1 and CREaro. Using the yeast one-hybrid approach to screen a human breast tissue hybrid cDNA expression library, we found that four orphan/nuclear receptors, ERR alpha-1, EAR-2, COUP-TFI and RAR gamma, bind to the S1 element, and that CREB1, Snail (SnaH) and Slug proteins bind to the CREaro element. Studies from this and other laboratories have revealed that in cancer tissue versus normal tissue, several positive regulatory proteins (e.g. ERR alpha-1 and CREB1) are present at higher levels and several negative regulatory proteins (e.g. EAR-2, COUP-TFI, RAR gamma, Snail and Slug proteins) are present at lower levels. This may explain why the activity of promoters II and I.3 is up regulated in cancer tissue. An understanding of the molecular mechanisms of aromatase expression between non-cancerous and cancerous breast tissue, at the transcriptional level, may help in the design of a therapy based on the suppression of aromatase expression in breast cancer tissue.
J Steroid Biochem Mol Biol 2002 Dec
PMID:Transcriptional regulation of aromatase expression in human breast tissue. 1265 Jul 5

Endometriosis, defined as the presence of endometrial glands and stroma outside of the uterine cavity, develops mostly in women of reproductive age and regresses after menopause or ovariectomy, suggesting that the growth is estrogen-dependent. Indeed, the lesions contain estrogen receptors (ER) as well as aromatase, an enzyme that catalyses the conversion of androgens to estrogens, suggesting that local estrogen production may stimulate the growth of lesions. The expression patterns of ER and progesterone receptors in endometriotic lesions are different from those in the eutopic endometrium. Moreover, estrogen metabolism, including the expression pattern of aromatase and the regulation of 17 beta-hydroxysteroid dehydrogenase type 2 (an enzyme responsible for the inactivation of estradiol to estrone), is altered in the eutopic endometrium of women with endometriosis, adenomyosis, and/or leiomyomas compared to that in the eutopic endometrium of women without disease. Immunostaining for P450arom in endometrial biopsy specimens diagnosed these diseases with sensitivity and specificity of 91 and 100%, respectively. This is applicable to the clinical diagnosis of endometriosis. The polymorphisms in the ER-alpha gene, the CYP19 gene encoding aromatase, and several other genes are associated with the risk of endometriosis. Studies of these will lead to better understandings of the etiology and pathophysiology of endometriosis.
J Steroid Biochem Mol Biol 2002 Dec
PMID:Endometriosis: the pathophysiology as an estrogen-dependent disease. 1265 Jul 11

A serum-free culture system has been developed in ruminants that allows gonadotrophin-responsive induction of oestradiol (E2) production by non-differentiated granulosa cells (GC) from small antral follicles. Critical determinants are dose of FSH and insulin-like growth factor (IGF), and the plating density of the GC. Over the first 16 h of culture when cells remained as a dispersed monolayer, expression declined in FSH receptors (FSHr) (P <0.001), IGF type 1 receptor (IGF-1r) (P <0.08) and p450 arom (CYP19, P <0.001). Characteristic GC clusters formed from 16 h and further enlarged between 24 and 48 h, accompanied by marked increases in FSHr (P <0.01), IGF-1r (P <0.05), and p450 arom (P <0.01) expression, and preceded induction and subsequent peak E2 production, at 96 and 144 h, respectively (P <0.01). In conclusion, isolation and dispersion of GC appears to induce reversion to an immature state resulting in loss of receptor expression. Re-establishment of cell-cell communications in the presence of FSH and IGF results in receptor up-regulation and induction of cellular differentiation.
Mol Cell Endocrinol 2003 May 30
PMID:Temporal relationships between FSH receptor, type 1 insulin-like growth factor receptor, and aromatase expression during FSH-induced differentiation of bovine granulosa cells maintained in serum-free culture. 1278 8

In the human placental syncytiotrophoblast, C(19) steroids are converted to estrogens by aromatase P450, product of the CYP19 gene. When human cytotrophoblasts, which lack the capacity to express aromatase, are cultured in 20% O(2), they spontaneously fuse to form a multinuclear syncytiotrophoblast and CYP19 expression is markedly induced. On the other hand, when cytotrophoblasts are cultured in 2% O(2), syncytiotrophoblast differentiation and induction of CYP19 expression are prevented. We previously observed that expression of the transcription factor Mash-2 (mammalian achaete/scute homologue 2), which is elevated in human cytotrophoblasts and maintained at elevated levels by hypoxia, declines with syncytiotrophoblast differentiation. Overexpression of Mash-2 prevents syncytiotrophoblast differentiation and induction of CYP19 expression. In the present study, we observed that unexpectedly immunoreactive Mash-2 protein was localized predominantly to the cytoplasm of human cytotrophoblasts. Elevated cytoplasmic levels of Mash-2 were maintained when trophoblasts were cultured in 2% O(2) and declined to undetectable levels upon culture in 20% O(2). Previously, we found that Mash-2 inhibited CYP19 promoter activity through sequences within a 350-bp region upstream and within placenta-specific exon I.1 containing three E boxes (E1 at -325 bp, 5'-CACTTG-3'; E2 at -58 bp, 5'-CACATG-3'; and E3 at +26 bp, 5'-CACGTG-3'). In this study, we found that trophoblast nuclear protein binding to these E boxes declined with syncytiotrophoblast differentiation in 20% O(2) and was induced by hypoxia; however, Mash-2 did not appear to bind to any of these E boxes. On the other hand, the basic helix-loop-helix leucine zipper transcription factors upstream stimulatory factors 1 and 2 (USF1 and USF2) did bind to E2 and E3 but not E1. Nuclear levels of USF1 and USF2 and DNA-binding activity declined with syncytiotrophoblast differentiation and were maintained at elevated levels by hypoxia and overexpression of Mash-2, whereas USF1 mRNA levels were unaffected. Finally, USF1 overexpression in cultured human trophoblasts markedly inhibited endogenous CYP19 expression, differentiation of cultured human trophoblast cells, and CYP19 promoter activity. These findings suggest that increased protein levels and DNA binding of USF1 and USF2 mediate the inhibitory effects of hypoxia and of Mash-2 on CYP19 gene expression in human placenta.
Mol Cell Biol 2003 Sep
PMID:USF1 and USF2 mediate inhibition of human trophoblast differentiation and CYP19 gene expression by Mash-2 and hypoxia. 1291 34

The CYP19 gene encodes for aromatase (P450arom), a key steroidogenic enzyme that catalyzes the final step of estrogen biosynthesis. Apart from rare mutations in CYP19 which result in severe phenotypes associated with estrogen insufficiency, little is known about whether common variation in CYP19 is associated with risk of hormone-related diseases. In this study, we employed a haplotype-based approach to search for common disease-associated variants in this candidate breast cancer susceptibility gene among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We utilized 74 densely spaced single-nucleotide polymorphisms (SNPs) (one every approximately 2.6 kb) spanning 189.4 kb of the CYP19 locus to characterize linkage disequilibrium (LD) and haplotype patterns among 69-70 individuals from each ethnic population. We detected four regions of strong LD (blocks 1-4) that were quite closely conserved across populations. Within each block there was a limited diversity of common haplotypes (5 to 10 with a frequency >/=5%) and most haplotypes were observed to be shared across populations. Twenty-five haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average Rh2=0.92) and genotyped in a breast cancer case-control study in the MEC (cases, n=1355; controls, n=2580). We first performed global tests for differences in risk according to the common haplotypes and observed significant haplotype-effects in block 2 [P=0.01; haplotypes 2b (OR=1.23; 95% CI, 1.07-1.40), 2d (OR=1.28; 95% CI, 1.01-1.62)]. We also found a common long-range haplotype comprised of block-specific haplotypes 2b and 3c to be associated with increased risk of breast cancer (haplotype 2b-3c: OR=1.31; 95% CI, 1.11-1.54). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.
Hum Mol Genet 2003 Oct 15
PMID:A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort. 1294 21

Steroid biosynthesis in ovary is enhanced by the orphan nuclear receptor, steroidogenic factor-1 (SF-1); however, we reported that liver receptor homolog-1 (LRH-1), a closely related receptor to SF-1, is also expressed in mouse ovary. To further investigate the role of LRH-1 in mouse ovary, we used in situ hybridization to identify the cell types that express LRH-1 versus SF-1, and carried out functional studies to determine the role of LRH-1 in the regulation of the human (h) ovary-specific CYP19 promoter. LRH-1 expression was found to be abundant and highly restricted to cells involved in estrogen biosynthesis-granulosa cells during the estrous cycle, and in corpora lutea (CL) of pregnancy. In contrast, SF-1 was expressed most highly in C(19)-steroid-producing theca cells and interstitium, and at low levels in granulosa and luteal cells. Transfection studies using granulosa cells demonstrated that LRH-1 is a potent regulator of both basal and forskolin-induced transcription of the ovary-specific hCYP19 promoter. This activity was dependent upon two nuclear receptor half-sites within the proximal hCYP19 promoter. Based on these findings, we propose that LRH-1 plays an important role as a competence factor in regulating aromatase, and thus estrogen biosynthesis, in ovary.
Mol Cell Endocrinol 2003 Sep 30
PMID:Expression of LRH-1 and SF-1 in the mouse ovary: localization in different cell types correlates with differing function. 1297 82


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