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The Journal of Steroid Biochemistry and... Jul 2016Aromatase and estrogen receptor α (ER) are two key proteins for the proliferation of endocrine-responsive and -resistant breast cancers. Aromatase is an enzyme involved... (Review)
Review
Aromatase and estrogen receptor α (ER) are two key proteins for the proliferation of endocrine-responsive and -resistant breast cancers. Aromatase is an enzyme involved in the conversion of androgen (such as testosterone) to estrogen (such as 17β-estradiol). It is also a very effective therapeutic target for the treatment of endocrine-responsive breast cancer. Comparing endocrine-responsive and -resistant breast cancer, aromatase protein levels do not change significantly. Aromatase activity; however, can be increased via PI3K/Akt/IGFR signaling pathways in endocrine resistant cells. The activity of aromatase has been reported to be modulated by phosphorylation. The ER is an important steroid nuclear receptor in the proliferation of both endocrine-responsive and -resistant cells. Although the mutation or amplification of ER can cause endocrine resistance, it is not commonly found. Some point mutations and translocation events have been characterized and shown to promote estrogen-independent growth. Phosphorylation by cross-talk with growth factor pathways is one of the main mechanisms for ligand-independent activation of ER. Taken together, both ER and aromatase are important in ER-dependent breast cancer and the development of endocrine resistance.
Topics: Animals; Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Breast; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Phosphatidylinositol 3-Kinases; Point Mutation; Proto-Oncogene Proteins c-akt; Receptors, Estrogen
PubMed: 26277097
DOI: 10.1016/j.jsbmb.2015.07.018 -
Endokrynologia Polska 2010Aromatase is a member of the cytochrome P450 superfamily that catalyzes the conversion of androgens (C(19)), namely testosterone and androstenedione, into oestrogens... (Review)
Review
Aromatase is a member of the cytochrome P450 superfamily that catalyzes the conversion of androgens (C(19)), namely testosterone and androstenedione, into oestrogens (C(18)), oestradiol, and oestrone, respectively. The enzyme is active in various tissues in both females and males, thus oestrogens are produced not only in gonads but also in extra-gonadal localizations such as brain, adipose tissue, breast, skin, and bone. Aromatase gene CYP19A1 located on chromosome 15 comprises nine coding exons and a number of alternative non-coding first exons that regulate tissue-specific expression. Studies on local regulation of aromatase expression and activity are important for understanding processes such as growth of oestrogen-dependent breast cancer. Rare clinical conditions of aromatase deficiency and excess have revealed some new and unexpected oestrogen functions in metabolism and bone health in both women and men. They were further studied using transgenic animal models such as aromatase knockout mice (ArKO) or (AROM+) mice overexpressing human aromatase. Research on aromatase was important for its practical outcome as it contributed to the development of aromatase inhibitors (AIs), an effective and safe group of drugs for the first-line endocrine therapy of breast cancer. Further studies are needed to establish AIs application in other oestrogen-dependent conditions, to overcome the resistance in breast cancer patients, and to develop tissue-specific selective inhibitors. (Pol J Endocrinol 2010; 61 (1): 126-134).
Topics: Animals; Aromatase; Aromatase Inhibitors; Bone and Bones; Breast Neoplasms; Estrogens; Female; Humans; Male; Mice; Polymorphism, Genetic
PubMed: 20205115
DOI: No ID Found -
Molecular and Cellular Endocrinology Feb 2022Testicular aromatase catalyzes the synthesis of estradiol, which contributes to regulation of porcine Sertoli cell proliferation and postpubertal maintenance of Sertoli...
Testicular aromatase catalyzes the synthesis of estradiol, which contributes to regulation of porcine Sertoli cell proliferation and postpubertal maintenance of Sertoli cell numbers. Although aromatase enzymatic activity decreases with age and is persistently reprogrammed by prepubertal treatment with the aromatase inhibitor letrozole, the molecular bases for regulation have not been identified. DNA methylation was examined as a potential regulatory mechanism using DNA from Leydig cells isolated from 16-, 40-, and 68-week-old boars and from 68- week-old littermates treated with the aromatase inhibitor, letrozole. Methylation levels of individual CpG dinucleotides located in the distal untranslated exon 1 of the relevant aromatase encoding gene, CYP19A3, were quite high in Leydig cell DNA, and increased further with maturity of boar (P < 0.05), while aromatase activity and transcript abundance decreased more than two-fold. However, reduced aromatase activity following letrozole treatment was not accompanied by altered DNA methylation. Testicular expression of miR378 was altered by prepubertal treatment with letrozole. The data provide evidence for two different epigenetic mechanisms that regulate aromatase expression and enzymatic activity in the boar testis.
Topics: Animals; Animals, Newborn; Aromatase; Aromatase Inhibitors; Cells, Cultured; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Letrozole; Leydig Cells; Male; Sertoli Cells; Swine; Testis
PubMed: 34856344
DOI: 10.1016/j.mce.2021.111526 -
Hormone Research 2009cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of... (Review)
Review
INTRODUCTION
cP450aromatase deficiency provides clues for the understanding of the role of aromatase in prepubertal and pubertal human health and disease. Placental aromatization of androgens protects the female fetus against the virilizing action of fetal androgens. After birth, the dual effect of aromatase deficiency, excessive androgens, and insufficient estrogens is responsible for a variable clinical picture. Nineteen cases of aromatase gene (CYP19) deficiency have been reported.
PHENOTYPE
Phenotype is dependent on sex and age. In newborns, aromatase deficiency should be considered in the etiology of 46,XX DSD, after ruling out congenital adrenal hyperplasia. In prepubertal aromatase deficient girls, high levels of ovarian androgens and gonadotropins facilitate the formation of ovarian cysts. Bone mineralization can be affected and bone aging is delayed. In pubertal girls, there is poor sexual development and abnormal virilization. The phenotype may be variable according to enzyme activity level. Insulin sensitivity may be abnormal in both men and women. Finally, aromatase might also play a role in the regulation of testicular cell mass in the newborn testis.
CONCLUSION
Adequate interpretation of clinical data should lead to the analysis of the CYP19 gene for diagnostic confirmation and implementation of appropriate management.
Topics: Adolescent; Androgens; Aromatase; Bone Development; Child; Female; Genitalia; Humans; Hypothalamo-Hypophyseal System; Infant; Infant, Newborn; Insulin Resistance; Lipids; Male; Models, Biological; Mutation; Phenotype; Pregnancy; Puberty
PubMed: 19844120
DOI: 10.1159/000249159 -
British Journal of Cancer Jan 2017Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal... (Review)
Review
Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment. Extensive translational research during the past two decades has elucidated the major pathways contributing to endocrine resistance and paved the way for clinical studies investigating the efficacy of novel drug combinations involving aromatase inhibitors and emerging drugable targets like mTOR, PI3K and CDK4/6. The present review summarises the basic research that provided the rationale for new drug combinations involving aromatase inhibitors and the main findings of pivotal clinical trials that have already started to change our way to treat hormone-sensitive MBC. The challenging situation of oestrogen receptor-positive and human epidermal growth factor receptor 2-positive (HER2+) MBC is also shortly reviewed to underline the complexity of the clinical scenario in the heterogeneous subgroups of hormone receptor-positive breast cancer patients and the increasing need for personalised medicine. Finally, we summarise some of the promising findings made with the combination of aromatase inhibitors with other potent endocrine treatment options like fulvestrant, a selective oestrogen receptor downregulator.
Topics: Antineoplastic Combined Chemotherapy Protocols; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Drugs, Investigational; Female; Humans; Molecular Targeted Therapy; Neoplasm Metastasis; Signal Transduction
PubMed: 27923036
DOI: 10.1038/bjc.2016.405 -
Nutrients Oct 2022Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme,...
Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme, 17-alpha-hydroxylase (Cyp17a1) expression. It has been demonstrated that Kelulut honey (KH) improves both female and male reproductive system anomalies in animal studies. Here, we examined the effects of isolated and combined KH, metformin, and clomiphene in improving folliculogenesis, aromatase, and steroidogenic enzyme profiles and ovarian histomorphology in letrozole-induced PCOS rats. Letrozole (1 mg/kg/day) was administered to female Sprague-Dawley (SD) rats for 21 days to induce PCOS. PCOS rats were subsequently divided into six experimental groups: untreated, treatment with metformin (500 mg/kg/day), clomiphene (2 mg/kg/day), KH (1 g/kg/day), combined KH (1 g/kg/day) and metformin (500 mg/kg/day), and combined KH (1 g/kg/day) and clomiphene (2 mg/kg/day). All treatments were given orally for 35 days. We found that KH was comparable with clomiphene and metformin in improving the expression of Cyp17a1 and Cyp19a1, apart from enhancing folliculogenesis both histologically and through the expression of folliculogenesis-related genes. Besides, the combination of KH with clomiphene was the most effective treatment in improving the ovarian histomorphology of PCOS rats. The effectiveness of KH in restoring altered folliculogenesis, steroidogenic, and aromatase enzyme profiles in PCOS warrants a future clinical trial to validate its therapeutic effect clinically.
Topics: Animals; Female; Rats; Aromatase; Clomiphene; Honey; Letrozole; Metformin; Polycystic Ovary Syndrome; Rats, Sprague-Dawley
PubMed: 36297046
DOI: 10.3390/nu14204364 -
Molecular and Cellular Endocrinology Jul 2021Estrogen signaling has been implicated in hormone-dependent breast cancer which constitutes >75% of breast cancer diagnosis and other malignancies. Aromatase, the key... (Review)
Review
Estrogen signaling has been implicated in hormone-dependent breast cancer which constitutes >75% of breast cancer diagnosis and other malignancies. Aromatase, the key enzyme involved in the synthesis of estrogen, is often dysregulated in breast cancers. This has led to the administration of aromatase-inhibitors (AIs), commonly used for hormone-dependent breast cancers. Unfortunately, the increasing development of acquired resistance to the current AIs and modulators of estrogen receptors, following initial disease steadiness, has posed a serious clinical challenge in breast cancer treatment. In this review we highlight historical and recent advances on the transcriptional and post-translational regulation of aromatase in both physiological and pathological contexts. We also discuss the different drug combinations targeting various tumor promoting cell signaling pathways currently being developed and tested both in laboratory settings and in the clinic.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Signal Transduction
PubMed: 33992735
DOI: 10.1016/j.mce.2021.111321 -
Frontiers in Neuroendocrinology Apr 2010Unlike that of mammals, the brain of teleost fish exhibits an intense aromatase activity due to the strong expression of one of two aromatase genes (aromatase A or... (Review)
Review
Unlike that of mammals, the brain of teleost fish exhibits an intense aromatase activity due to the strong expression of one of two aromatase genes (aromatase A or cyp19a1a and aromatase B or cyp19a1b) that arose from a gene duplication event. In situ hybridization, immunohistochemistry and expression of GFP (green fluorescent protein) in transgenic tg(cyp19a1b-GFP) fish demonstrate that aromatase B is only expressed in radial glial cells (RGC) of adult fish. These cells persist throughout life and act as progenitors in the brain of both developing and adult fish. Although aromatase B-positive radial glial cells are most abundant in the preoptic area and the hypothalamus, they are observed throughout the entire central nervous system and spinal cord. In agreement with the fact that brain aromatase activity is correlated to sex steroid levels, the high expression of cyp19a1b is due to an auto-regulatory loop through which estrogens and aromatizable androgens up-regulate aromatase expression. This mechanism involves estrogen receptor binding on an estrogen response element located on the cyp19a1b promoter. Cell specificity is achieved by a mandatory cooperation between estrogen receptors and unidentified glial factors. Given the emerging roles of estrogens in neurogenesis, the unique feature of the adult fish brain suggests that, in addition to classical functions on brain sexual differentiation and sexual behaviour, aromatase expression in radial glial cells could be part of the mechanisms authorizing the maintenance of a high proliferative activity in the brain of fish.
Topics: Animals; Aromatase; Base Sequence; Brain; Cholesterol Side-Chain Cleavage Enzyme; Embryo, Nonmammalian; Fishes; Gene Expression Regulation; Gonads; Molecular Sequence Data; Neurogenesis; Phylogeny; Receptors, Estrogen; Seasons; Sex Differentiation; Sexual Behavior, Animal; Steroid 17-alpha-Hydroxylase
PubMed: 20116395
DOI: 10.1016/j.yfrne.2010.01.003 -
Aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole and vorozole templates.ChemMedChem Aug 2011Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against...
Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase-sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub-nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole-derived sulfamates and a vorozole-based sulfamate were designed and biologically evaluated in JEG-3 cells to reveal structure-activity relationships. Amongst achiral and racemic compounds, 2-bromo-4-(2-(4-cyanophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC₅₀ =0.87 nM; STS: IC₅₀ =593 nM). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X-ray crystallography. Following conversion to their corresponding sulfamates, the S-(+)-enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC₅₀ =0.52 nM; STS: IC₅₀ =280 nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.
Topics: Aromatase; Aromatase Inhibitors; Binding Sites; Catalytic Domain; Cell Line, Tumor; Computer Simulation; Crystallography, X-Ray; Enzyme Activation; Humans; Letrozole; Nitriles; Stereoisomerism; Steryl-Sulfatase; Structure-Activity Relationship; Sulfonic Acids; Triazoles
PubMed: 21608133
DOI: 10.1002/cmdc.201100145 -
Scientific Reports Mar 2021Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase...
Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC and were therefore selected for further assays. In silico molecular modeling against ER and aromatase was performed for the three compounds. In vivo estrogenic and anti-estrogenic assays confirmed an anti-estrogenic activity for the isolates. Moreover, naringenin, naringin and quercetin demonstrated in vitro inhibitory potential against aromatase enzyme along with anticancer potential in vivo, as evidenced by decreased tumor volumes. Reduction in aromatase levels in solid tumors was also observed in treated groups. Overall, this study suggests an antitumor potential for naringenin, naringin and quercetin isolated from citrus peels in breast cancer via possible modulation of estrogen signaling and aromatase inhibition suggesting their use in pre- and post-menopausal breast cancer patients, respectively.
Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Citrus; Estrogen Receptor Modulators; Female; Humans; Mice; Plant Extracts; Xenograft Model Antitumor Assays
PubMed: 33782546
DOI: 10.1038/s41598-021-86599-z