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Molecular and Cellular Biochemistry Jun 2021The regulation of aromatase, an enzyme involved in the biosynthesis of estrogen in normal and cancer cells, has been associated with growth factor signaling and immune... (Review)
Review
The regulation of aromatase, an enzyme involved in the biosynthesis of estrogen in normal and cancer cells, has been associated with growth factor signaling and immune response modulation. The tissue-specific regulatory roles of these factors are of particular importance as local aromatase expression is strongly linked to cancer development/progression and disease outcomes in patients. Therefore, aromatase has become a chemotherapeutic target and aromatase inhibitors (AIs) are used in the clinic for treating hormone-dependent cancers. Although AIs have shown promising results in the treatment of cancers, the emerging increase in AI-resistance necessitates the development of new and improved targeted therapies. This review discusses the role of tumor and stromal-derived growth factors and immune cell modulators in regulating aromatase. Current single-agent and combination therapies with or without AIs targeting growth factors and immune checkpoints are also discussed. This review highlights recent studies that show new connections between growth factors, mediators of immune response, and aromatase regulation.
Topics: Animals; Aromatase; Aromatase Inhibitors; Humans; Neoplasm Proteins; Neoplasms
PubMed: 33599895
DOI: 10.1007/s11010-021-04099-0 -
Frontiers in Neuroendocrinology Apr 2022This review explores the role of aromatase in the brain as illuminated by a set of conserved network-level connections identified in several vertebrate taxa.... (Review)
Review
This review explores the role of aromatase in the brain as illuminated by a set of conserved network-level connections identified in several vertebrate taxa. Aromatase-expressing neurons are neurochemically heterogeneous but the brain regions in which they are found are highly-conserved across the vertebrate lineage. During development, aromatase neurons have a prominent role in sexual differentiation of the brain and resultant sex differences in behavior and human brain diseases. Drawing on literature primarily from birds and rodents, we delineate brain regions that express aromatase and that are strongly interconnected, and suggest that, in many species, aromatase expression essentially defines the Social Behavior Network. Moreover, in several cases the inputs to and outputs from this core Social Behavior Network also express aromatase. Recent advances in molecular and genetic tools for neuroscience now enable in-depth and taxonomically diverse studies of the function of aromatase at the neural circuit level.
Topics: Animals; Aromatase; Brain; Female; Male; Neurons; Sex Characteristics; Social Behavior
PubMed: 34942232
DOI: 10.1016/j.yfrne.2021.100973 -
Journal of Steroid Biochemistry 1987Aromatase catalyzes the conversion of androgens to estrogens through a series of monooxygenations to achieve the 19-desmolation and aromatization of the neutral steroid... (Comparative Study)
Comparative Study Review
Aromatase catalyzes the conversion of androgens to estrogens through a series of monooxygenations to achieve the 19-desmolation and aromatization of the neutral steroid ring-A structure. We have separated two forms of aromatase, a major (P2a) and a minor (P3) form, from human term placenta through solubilization and chromatography. Partially purified aromatase in each form was immunoaffinity chromatographed to give a single band (SDS-PAGE) cytochrome P-450 of 55 kDa, utilizing a mouse monoclonal anti-human placental aromatase cytochrome P-450 IgGi (MAb3-2C2) which is capable of suppressing placental aromatase activity. The purified cytochrome P-450 showed specific aromatase activity of 25-30 nmol/min per mg with Km of 20-30 nM for androstenedione on reconstitution with NADPH-cyt P-450 reductase and dilauroyl L-alpha-phosphatidylcholine. This one step represents a higher than 100-fold purification with maintenance of the same Km. The stability analysis showed a half-life of more than 5 yr for solubilized aromatase and 2 months for the aromatase cytochrome P-450 on storage at -90 degrees C. Contrary to the recent claim that estrogen biosynthesis by reconstituted human placental cytochrome P-450 is by trans-diaxial 1 alpha,2 beta-hydrogen elimination, all of our partially purified forms and reconstituted aromatase synthesized estrogens by cis-1 beta, 2 beta-hydrogen elimination. Use of purified aromatase and [19-3H3, 4-14C]androstenedione led us to discover a metabolic switching by aromatase to 2 beta-hydroxylation of androgen. Results of the MAb3-2C2 suppression of aromatase activity in different species and tissues including human, baboons, horses, cows, pigs and rats indicated the presence of various isozymes of aromatase.
Topics: Androgens; Animals; Aromatase; Carbon Radioisotopes; Cytochrome P-450 Enzyme System; Female; Humans; Isoenzymes; Placenta; Pregnancy; Tritium
PubMed: 3320558
DOI: 10.1016/0022-4731(87)90150-6 -
Annual Review of Physiology 2002There is growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on... (Review)
Review
There is growing awareness that androgens and estrogens have general metabolic roles that are not directly involved in reproductive processes. These include actions on vascular function, lipid and carbohydrate metabolism, as well as bone mineralization and epiphyseal closure in both sexes. In postmenopausal women, as in men, estrogen is no longer solely an endocrine factor but instead is produced in a number of extragonadal sites and acts locally at these sites in a paracrine and intracrine fashion. These sites include breast, bone, vasculature, and brain. Within these sites, aromatase action can generate high levels of estradiol locally without significantly affecting circulating levels. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis. The levels of these androgenic precursors decline markedly with advancing age in women, possible from the mid-to-late reproductive years. This may be a fundamental reason why women are at increased risk for bone mineral loss and fracture, and possibly decline of cognitive function, compared with men. Aromatase expression in these various sites is under the control of tissue-specific promotors regulated by different cohorts of transcription factors. Thus in principle, it should be possible to develop selective aromatase modulators (SAMs) that block aromatase expression, for example, in breast, but allow unimpaired estrogen synthesis in other tissues such as bone.
Topics: Animals; Aromatase; Estrogens; Humans; Neoplasms
PubMed: 11826265
DOI: 10.1146/annurev.physiol.64.081601.142703 -
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 Bioscience : a Journal and... Aug 1998Estrogens play an important role in breast cancer development. Aromatase (CYP19), a cytochrome P450, is the enzyme that synthesizes estrogens. Aromatase is expressed at... (Review)
Review
Estrogens play an important role in breast cancer development. Aromatase (CYP19), a cytochrome P450, is the enzyme that synthesizes estrogens. Aromatase is expressed at a higher level in human breast cancer tissue than in normal breast tissue using enzyme activity measurement, immunocytochemistry, and RT-PCR analysis. Cell culture, animal experiments using aromatase-transfected breast cancer cells, and transgenic mouse studies have demonstrated that in situ produced estrogen plays a more important role than circulating estrogens in breast tumor promotion. In addition, tumor aromatase has been shown to stimulate breast cancer growth in both an autocrine and a paracrine manner. RT-PCR and gene transcriptional studies have revealed that aromatase promoter switches from a glucocorticoid-stimulated promoter, I.4, in normal tissue to cAMP-stimulated promoters, I.3 and II, in cancereous tissue. Suppression of in situ estrogen biosynthesis can be achieved by the prevention of aromatase expression or by the inhibition of aromatase activity in breast tumors. While the control mechanism of aromatase expression in breast cancer tissue is not yet fully understood, aromatase-inhibitor therapy is considered for second-line treatment in patients who fail anti-estrogen therapy. Twenty to thirty percent of the patients who fail anti-estrogen treatment respond to aromatase-inhibitor treatment. Several potent and selective aromatase inhibitors have been developed and used to treat breast cancer. The binding nature of various aromatase inhibitors has been examined by computer modeling, site-directed mutagenesis of aromatase, and inhibition kinetics. The enzyme structure-function studies have led to the development of a computer model of the active site region of human aromatase. The model is used to evaluate the interaction of phytoestrogens such as flavones and isoflavones with aromatase. The study provides a molecular basis as to why isoflavones are significantly poorer inhibitors of aromatase than flavones. The phytoestrogen studies will help to determine which fruits and vegetables (those containing the appropriate phytoestrogens) should be included in the diet of postmenopausal women in order to reduce the incidence for breast cancer by inhibiting estrogen biosynthesis in breast tissue.
Topics: Animals; Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Structure-Activity Relationship
PubMed: 9696881
DOI: 10.2741/a333 -
Journal of Chemical Neuroanatomy Dec 2018Aromatase (Cyp19a1) is a steroidogenic enzyme that functions to convert aromatizable androgens into bioactive estrogens. The teleost brain is known to have the highest... (Review)
Review
Aromatase (Cyp19a1) is a steroidogenic enzyme that functions to convert aromatizable androgens into bioactive estrogens. The teleost brain is known to have the highest levels of aromatase activity among vertebrates, yet we know relatively little about the function of local estrogen production in teleost behavior. This review compares and contrasts the findings from behavioral studies in the visual, auditory, electrosensory, and olfactory systems, with expression studies in the brain and peripheral nervous system to identify pathways for aromatase effects on teleost behavior. I will first describe aromatase expression at the cellular level in the teleost brain. I will then review evidence for an effect of aromatase activity in sensory perception across different communication systems, followed by a comparison of its effects in the signal production circuitry of vocal and electrogenic teleosts. The findings presented demonstrate that aromatase expression is well conserved in the sensory afferent nerve fibers across communication systems, despite the paucity of study to date on the effects of locally produced estrogens in sensory perception. It is also apparent that there are numerous other locations of aromatase expression within sensory pathways, drawing attention to the need for more localized inhibition studies to understand the function of local estrogen production in distinct regions. The findings in the last section of this review show that differences in vocal call production in the plainfin midshipman fish likely involve differences in aromatase expression in the hindbrain control nucleus, whilst this relationship does not appear to be conserved in the brown ghost knifefish for electromotor production. Therefore, local estrogen function in signaling behavior at the organismal level likely differs between these communication systems, though its effects at the cellular level remain to be determined.
Topics: Animals; Aromatase; Behavior, Animal; Brain; Fishes; Social Behavior
PubMed: 30336206
DOI: 10.1016/j.jchemneu.2018.10.004 -
Physiology (Bethesda, Md.) Jul 2016Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known... (Review)
Review
Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.
Topics: Animals; Aromatase; Aromatase Inhibitors; Brain; Disease; Estrogens; Female; Homeostasis; Human Development; Humans; Male
PubMed: 27252161
DOI: 10.1152/physiol.00054.2015 -
Clinical and Experimental Rheumatology Jul 2023Oestrogen deficiency is a rare disease and leads inter alia to arthralgia and osteoporosis in men. The clinical relevance of aromatase to a functioning male metabolism... (Review)
Review
OBJECTIVES
Oestrogen deficiency is a rare disease and leads inter alia to arthralgia and osteoporosis in men. The clinical relevance of aromatase to a functioning male metabolism has become evident since 1991, when cases of patients with oestrogen deficiency caused by aromatase mutation were first described. Only few cases are known so far, which will now be presented in a case report and review of the literature.
METHODS
All available publications since the first description in 1991 dealing with loss-of-function aromatase mutation in men were summarised and our case report was added.
RESULTS
The mutations that cause the aromatase protein to lose function leads to a rather heterogeneous clinical picture. It is, however, clear that oestrogens play a central role in male patients, especially in bone metabolism. Most frequently, tall stature, unclosed epiphyseal joints, and osteoporosis are detected in affected individuals as a consequence of the change in hormonal status.
CONCLUSIONS
As low oestrogen is associated with arthralgia, patients with aromatase mutation may be referred to a rheumatologist. Despite aromatase deficiency being a rare disease, the study of the effects of oestrogen on male bone development provides important insights for endocrine bone regulation. It has been demonstrated that androgens alone are not sufficient for adequate skeletal development in males. The described effects of loss of oestrogens are known from the aromatase inhibitor therapy in breast cancer treatment. This work highlights the important role of oestrogens in individual health and disease in men. Molecular effects of oestrogens on bone metabolism are summarised.
Topics: Humans; Male; Aromatase; Rare Diseases; Estrogens; Osteoporosis; Mutation
PubMed: 36622109
DOI: 10.55563/clinexprheumatol/gj7xal -
Advances in Clinical Chemistry 2011Aromatase is a specific component of the cytochrome P450 enzyme system that is responsible for the transformation of C19 androgen precursors into C18 estrogenic... (Review)
Review
Aromatase is a specific component of the cytochrome P450 enzyme system that is responsible for the transformation of C19 androgen precursors into C18 estrogenic compounds. This enzyme is encoded by the CYP19A1 gene located at chromosome 15q21.2, that is expressed in ovary and testis not only but also in many extraglandular sites such as the placenta, brain, adipose tissue, and bone. The regulation of the level and activity of aromatase determines the levels of estrogens that have endocrine, paracrine, and autocrine effects on target issues including bone. Importantly, extraglandular aromatization of circulating androgen precursors is the major source of estrogen not only in men (since only 15% of circulating estradiol is released directly by the testis) but also in women after the menopause. Several lines of clinical and experimental evidence now clearly indicate that aromatase activity and estrogen production are necessary for longitudinal bone growth, attainment of peak bone mass, the pubertal growth spurt, epiphyseal closure, and normal bone remodeling in young individuals. Moreover, with aging, individual differences in aromatase activity and thus in estrogen levels may significantly affect bone loss and fracture risk in both genders.
Topics: Animals; Aromatase; Bone Density; Bone Remodeling; Bone and Bones; Estrogens; Female; Humans; Male; Organ Specificity; Osteoporosis
PubMed: 21874760
DOI: 10.1016/b978-0-12-387025-4.00006-6