Disease relevance of CYP19A1

• We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs [1].
• Linked variants in CYP19A1 (intron 4 [TTTA]n, intron 4 [TCT] insertion/deletion, exon 10 C/T) are related to some hormone levels and, based on two studies, to risk of endometrial cancer [2].
• Like hypoxia, inhibitory effects of proteasome inhibitors on hCYP19 expression were mediated by increased binding of USF1/2 to the E-boxes [3].
• Aromatase plays a critical role in breast cancer development by converting androgen to estrogen [4].
• Steroid hormone receptor expression observed in vitro paralleled that seen in cervical carcinomas expressing aromatase [5].
• Definition of this mechanism further may assist in designing inhibitors of aromatase specific for leiomyoma tissue [6].
• We observed that progesterone antagonized the stimulatory effects of cAMP and IL-1beta on aromatase, COX-2, and HER-2/neu expression in T47D breast cancer cells [7].

Psychiatry related information on CYP19A1

• Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer's disease [8].
• In the human, in contrast to nonprimate vertebrates, aromatase deficiency and estrogen resistance (alpha) does not seem to affect gender identity or psychosexual development [9].
• However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism [10].
• These results suggest that variation in the gene for this subunit of the aromatase enzyme complex is not likely to be a major factor in the development of individual differences in male sexual orientation [11].
• The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no role here [12].

High impact information on CYP19A1

• Aromatase inhibitors as adjuvant therapy for postmenopausal patients with early stage breast cancer [13].
• Using this method, we show that the interaction of genes on chromosomes 2 (NIDDM1) and 15 (near CYP19) makes a contribution to susceptibility to type 2 diabetes in Mexican Americans from Starr County, Texas [14].
• Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency [15].
• Effect of testosterone and estradiol in a man with aromatase deficiency [16].
• An aromatase-producing sex-cord tumor resulting in prepubertal gynecomastia [17].

Chemical compound and disease context of CYP19A1

• In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression [1].
• E10 cells specifically express GFP when ER is activated by estrogen or by coculture with adipose stromal cells isolated from breast tumor tissues in the presence of testosterone, a substrate for aromatase [18].
• Aromatase is the enzyme responsible for the conversion of androgens into estrogens, and synthetic aromatase inhibitors such as letrozole, anastrozole, and exemestane have proven to be effective endocrine regimens for ER-positive breast cancer [19].
• These results demonstrate that coumarins (a common type of phytochemical) or their derivatives can be potent inhibitors of aromatase and may be useful in suppressing aromataseand ER-positive breast tumors [19].
• PURPOSE: Prognostic significance of the intratumoral mRNA expression of three enzymes related to in situ estrogen biosynthesis, i.e., aromatase, sulfatase, and 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), was evaluated in patients with invasive breast cancer [20].
• In patients with hormone receptor-positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3' untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy [21].

Biological context of CYP19A1

• RESULTS: In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1 [22].
• Results indicate the need to study other variants and haplotypes in these genes, particularly CYP17A1 and CYP19A1, as well as variants in other genes involved in hormone biosynthesis and metabolism pathways [2].
• When cultured in 20% O(2), human cytotrophoblasts fuse to form the syncytiotrophoblast with marked induction of hCYP19 (aromatase) gene expression [3].
• Thus, early in gestation when the placenta is relatively hypoxic, increased USF1/2 may block trophoblast differentiation and hCYP19 gene expression [3].
• In cells cultured in 20% O(2), proteasome inhibitors increased USF1/2 protein levels and blocked spontaneous induction of hCYP19 expression, cell fusion, and differentiation [3].

Anatomical context of CYP19A1

• Circulating levels of estradiol in women are controlled by follicle-stimulating hormone (FSH), which regulates transcription of the aromatase gene (CYP19A1) in ovarian granulosa cells [23].
• In conclusion, testosterone inhibited VCAM-1 mRNA and protein expression in HUVEC by its conversion to estradiol via the enzyme aromatase present in the endothelial cells [24].
• When cultured in 2% O(2), cytotrophoblast fusion and induced hCYP19 expression are prevented [3].
• Aromatase gene expression levels in adipose stromal cells did not always correlate with their ability to induce GFP [18].
• Aromatase is expressed in breast adipose tissue through the use of a distal, cytokine-responsive promoter (promoter I.4) [25].

Associations of CYP19A1 with chemical compounds

• This may have a potential effect on the choice of tamoxifen versus aromatase inhibitors as adjuvant endocrine therapy [26].
• Aromatase inhibitor letrozole also inhibited growth at 10,000-fold higher concentration than required for MCF-7Ca cells, whereas anastrozole, exemestane, formestane, and tamoxifen were ineffective at 100 nmol/L [27].
• Treatment of adipose stromal cells with dexamethasone, a stimulator of aromatase gene expression, resulted in an increase in the expression of GFP in E10 cells in the coculture [18].
• In addition, aromatase induction in MCF-7 cells could also be suppressed by PD153035 hydrochloride [4].
• In a recent study, we have found that 4-benzyl-3-(4'-chlorophenyl)-7-methoxycoumarin is a potent competitive inhibitor of aromatase with respect to the androgen substrate [19].

Physical interactions of CYP19A1

• Additionally, beta-catenin is present in transcription complexes assembled on the endogenous gonad-specific CYP19A1 promoter, as evidenced by chromatin immunoprecipitation assays [23].
• These findings suggest that treatments targeted at growth factor signalling pathways may be useful in patients acquiring resistance to oestrogen deprivation with aromatase inhibitors and that the pure anti-oestrogen ICI 182,780 may also be effective by blocking or destabilizing ER and hence disrupting cross-talk [28].
• Stimulation of aromatase P450 promoter (II) activity in endometriosis and its inhibition in endometrium are regulated by competitive binding of steroidogenic factor-1 and chicken ovalbumin upstream promoter transcription factor to the same cis-acting element [29].
• PGE2 increased GATA-4 binding to the Cyp19 promoter [30].
• Experiments carried out with different models including turtles, crocodilians and lizards have demonstrated the implication of estrogens and the key role played by aromatase (the enzyme complex that converts androgens to estrogens) in ovary differentiation during TSP and in maintenance of the ovarian structure after TSP [31].

Enzymatic interactions of CYP19A1

• Aromatase and cholesterol side-chain cleaving P450 mRNAs, proteins, and activities are measurable in human placentas and do not seem to be affected by maternal cigarette smoking [32].
• In human placenta the enzyme complex aromatase catalyzes the conversion of androgens to estrogens and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) mediates the reversible interconversion of, e.g. estrone to estradiol [33].

Regulatory relationships of CYP19A1

• Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells [34].
• These studies demonstrate that Cox-2 directly regulates gene expression of specific aromatase promoter regions and regulates aromatase enzyme activity [35].
• Aromatase levels in breast cancer cells are enhanced by prostaglandins and reduced by COX inhibitors [36].
• The use of promoter I.4 for aromatase expression in adipose tissue has been recently observed to be regulated by members of the interleukin-6 (IL-6) cytokine family [37].
• Ad4BP/SF-1 regulates cyclic AMP-induced transcription from the proximal promoter (PII) of the human aromatase P450 (CYP19) gene in the ovary [38].

Other interactions of CYP19A1

• In the second trimester, increased O(2) tension promotes proteasomal degradation of USF1/2, resulting in syncytiotrophoblast differentiation and induction of hCYP19 expression [3].
• Overexpression of Mash-2 prevents syncytiotrophoblast differentiation and induction of CYP19 expression [39].
• The aromatase activity in the ER alpha-transfected SK-BR-3 cells could also be induced by environmental chemicals that were known to have an estrogen-like activity [4].
• The aromatase C/C genotype together with a longer AR was also more frequent among controls (55%) than cases (41%; age- and BMI-adjusted OR, 0.51; 95% CI, 0.30-0.89) [40].
• These results were consistent with enzyme activity data, suggesting that the effect of COX inhibitors on aromatase begins at the transcriptional level [34].
• In endometrial stromal cells and the human endometrial surface epithelial (HES) cell line, induction of aromatase mRNA by A4 was associated with increased expression of SF-1 [41].

Analytical, diagnostic and therapeutic context of CYP19A1

• Aromatase inhibitors inhibited the induction of GFP expression in the coculture, but the sensitivities to the drugs varied among the individual cases [18].
• In addition, through a matrigel thread three-dimensional cell culture, this compound was shown to behave like known aromatase inhibitors that suppress the proliferation of aromatase and estrogen receptor positive MCF-7aro breast cancer cells [19].
• Ovarian endometrioma tissue was chopped into small pieces, and two exon 1-specific transcripts of aromatase P450 (PII-specific and I.4-specific transcripts) were quantified using competitive RT-PCR [42].
• We evaluated the expression of aromatase and 17 beta-HSD type 1 by immunohistochemistry in 41 cases of invasive breast carcinoma (19 lobular and 22 ductal) [43].
• Real-time PCR analysis of aromatase gene expression showed a significant decrease in mRNA levels when compared with control for all agents [34].

References