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Recent Progress in Hormone Research 2002Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of... (Review)
Review
Endocrine adjuvant therapy for breast cancer in recent years has focussed primarily on the use of tamoxifen to inhibit the action of estrogen in the breast. The use of aromatase inhibitors has found much less favor due to poor efficacy and unsustainable side effects. Now, however, the situation is changing rapidly with the introduction of the so-called phase III inhibitors, which display high affinity and specificity towards aromatase. These compounds have been tested in a number of clinical settings and, almost without exception, are proving to be more effective than tamoxifen. They are being approved as first-line therapy for elderly women with advanced disease. In the future, they may well be used not only to treat young, postmenopausal women with early-onset disease but also in the chemoprevention setting. However, since these compounds inhibit the catalytic activity of aromatase, in principle, they will inhibit estrogen biosynthesis in every tissue location of aromatase, leading to fears of bone loss and possibly loss of cognitive function in these younger women. The concept of tissue-specific inhibition of aromatase expression is made possible by the fact that, in postmenopausal women when the ovaries cease to produce estrogen, estrogen functions primarily as a local paracrine and intracrine factor. Furthermore, due to the unique organization of tissue-specific promoters, regulation in each tissue site of expression is controlled by a unique set of regulatory factors. These factors are potential targets for the design of selective aromatase modulators, which could selectively inhibit aromatase expression in breast with the same efficacy as the phase III inhibitors of activity but leave expression in other local sites such as bone and brain untouched.
Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Enzyme Inhibitors; Estrogens; Female; Humans
PubMed: 12017550
DOI: 10.1210/rp.57.1.317 -
Seminars in Reproductive Medicine Feb 2004The recent studies on humans with a defective gene that encodes aromatase p450 (p450arom) and aromatase knockout (ArKO) mice with a disrupted p450arom gene uncovered... (Review)
Review
The recent studies on humans with a defective gene that encodes aromatase p450 (p450arom) and aromatase knockout (ArKO) mice with a disrupted p450arom gene uncovered many interesting aspects of physiology. Aromatase-deficient humans and ArKO mice continue to serve as invaluable models for us to study the roles of estrogen in normal and abnormal functions of several tissues. These roles will be discussed in detail in the following review article.
Topics: Animals; Aromatase; Disease Models, Animal; Estrogens; Humans; Metabolism, Inborn Errors; Mice; Mice, Knockout; Mutation
PubMed: 15083378
DOI: 10.1055/s-2004-823024 -
Seminars in Reproductive Medicine Feb 2004Aromatase p450 (p450arom) catalyzes the formation of estrogen in several human tissues under the control of alternatively used promoters. Each promoter is regulated by a... (Review)
Review
Aromatase p450 (p450arom) catalyzes the formation of estrogen in several human tissues under the control of alternatively used promoters. Each promoter is regulated by a distinct signaling pathway in a tissue- and hormone-specific manner. This article reviews these regulatory mechanisms in the ovary, adipose tissue, placenta, bone, brain, and various malignant cells. Moreover, the physiological and pathologic impacts of local estrogen biosynthesis in contrast to circulating estrogen or estrogen-responsive human tissues are discussed.
Topics: Aromatase; Estrogens; Gene Expression; Humans; Neoplasms; Tissue Distribution
PubMed: 15083377
DOI: 10.1055/s-2004-823023 -
Trends in Endocrinology and Metabolism:... 2000In contrast to normal endometrium, the expression of aromatase is aberrant in endometriosis and is stimulated by prostaglandin E2 (PGE2). This results in local... (Review)
Review
In contrast to normal endometrium, the expression of aromatase is aberrant in endometriosis and is stimulated by prostaglandin E2 (PGE2). This results in local production of estrogen, which induces PGE2 formation and establishes a positive feedback cycle. Another abnormality in endometriosis--deficient 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) type 2 expression--impairs the inactivation of estradiol (E2) to estrone (E1). These molecular aberrations collectively favor accumulation of increasing quantities of E2, and PGE2 in endometriosis. The clinical relevance of these findings was exemplified by the successful treatment of an unusually aggressive case of postmenopausal endometriosis with an aromatase inhibitor.
Topics: Aromatase; Endometriosis; Female; Humans
PubMed: 10652502
DOI: 10.1016/s1043-2760(99)00216-7 -
Progress in Medicinal Chemistry 1996
Review
Topics: Aromatase; Aromatase Inhibitors; Molecular Structure; Steroids
PubMed: 8776943
DOI: 10.1016/s0079-6468(08)70305-9 -
Endocrine Journal Jul 2008It is well-known that estrogens are closely involved in the growth of human breast carcinomas, and that the great majority of breast carcinoma express estrogen... (Review)
Review
It is well-known that estrogens are closely involved in the growth of human breast carcinomas, and that the great majority of breast carcinoma express estrogen receptors. Recent studies have demonstrated that estrogens are locally produced and act on the breast carcinoma tissue. Among these pathways, aromatase is a key enzyme for intratumoral production of estrogens in breast carcinomas, and aromatase inhibitors are currently used in the breast carcinoma in postmenopausal women as an estrogen deprivation therapy. This review summarizes the results of recent studies on the expression and regulation of aromatase in breast carcinoma tissues, and discusses the potential biological and/or clinical significance of aromatase. Aromatase is abundantly expressed in various cell types, such as carcinoma cells, intratumoral stromal cells, and adipocytes adjacent to the carcinoma, in breast carcinoma tissues. Further, a key regulator for aromatase expression differed according to cell type. In addition, aromatase suppressed in situ production of bioactive androgen, 5alpha-dihydrotestosterone (DHT), in breast carcinoma. Aromatase inhibitors may thus have additional antiproliferative effects through increasing local DHT concentration with estrogen deprivation.
Topics: Aromatase; Breast Neoplasms; Carcinoma; Estrogens; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Gonadal Steroid Hormones; Humans; Models, Biological; Neoplasms, Hormone-Dependent; Osmolar Concentration; Tissue Distribution
PubMed: 18480557
DOI: 10.1507/endocrj.k07e-053 -
Journal of Neuroendocrinology Feb 2018Brain expression of the enzyme P450-aromatase has been studied extensively. Subsequent to the aromatisation hypothesis having established brain aromatase as a key factor... (Review)
Review
Brain expression of the enzyme P450-aromatase has been studied extensively. Subsequent to the aromatisation hypothesis having established brain aromatase as a key factor to convert gonadal testosterone to oestradiol, several studies have investigated the regulation of aromatase during the critical period of brain sexual differentiation. We review previous and recent findings concerning regulation of aromatase. The role of gonadal hormones, sex chromosome genes and neurosteroids is analysed in terms of their contribution to aromatase expression, as well as implications for the organisational effect of steroids during development.
Topics: Animals; Aromatase; Brain; Female; Gene Expression Regulation, Developmental; Gonadal Steroid Hormones; Male; Sex Differentiation
PubMed: 28891264
DOI: 10.1111/jne.12535 -
Mini Reviews in Medicinal Chemistry 2016Local estrogen production from aromatase-mediated conversion of androgens is an important mechanism of autocrine growth stimulation in hormone-dependent breast cancers.... (Review)
Review
Local estrogen production from aromatase-mediated conversion of androgens is an important mechanism of autocrine growth stimulation in hormone-dependent breast cancers. The control mechanism of aromatase enzymatic activity in recent years has been demonstrated to be more complex than previously identified. Indeed, it is well known that aromatase expression is regulated at the transcriptional level through the alternative use of tissue-specific promoters, whereas it has become clear that the activity of this enzyme is also controlled by post-transcriptional modifications, such as phosphorylation processes. This paper presents a selective review of the novel findings in this area showing phosphorylation/dephosphorylation of aromatase as a switch to rapidly modulate its enzymatic activity. Particularly, we describe studies conducted in our laboratories, focusing on the role of estrogens in modulating aromatase activity in estrogen-dependent breast cancer cells. Two separate mechanisms are described. First, 17β-estradiol (E2), through c-Src kinase, is able to enhance tyrosine phosphorylation levels of aromatase protein and increases its enzymatic activity and estrogen biosynthesis. Secondly, E2, through the activation of PI3K/Akt pathway, impairs the ability of the tyrosine phosphatase PTP1B to dephosphorylate aromatase, resulting in a consequent enhanced phosphorylation and activity of the aromatase protein itself. These new controls of aromatase function provide insights into the mechanisms through which local estrogen production can be altered in breast cancer tissues. They also offer a vast array of possibilities for identifying different cell signalings that should be targeted in novel therapeutic strategies for breast cancer treatment.
Topics: Animals; Aromatase; Breast Neoplasms; Female; Humans; Phosphorylation
PubMed: 26996624
DOI: 10.2174/1389557516666160321113041 -
Cellular and Molecular Neurobiology May 2019The modulation of brain function and behavior by steroid hormones was classically associated with their secretion by peripheral endocrine glands. The discovery that the... (Review)
Review
The modulation of brain function and behavior by steroid hormones was classically associated with their secretion by peripheral endocrine glands. The discovery that the brain expresses the enzyme aromatase, which produces estradiol from testosterone, expanded this traditional concept. One of the best-studied roles of brain estradiol synthesis is the control of reproductive behavior. In addition, there is increasing evidence that estradiol from neural origin is also involved in a variety of non-reproductive functions. These include the regulation of neurogenesis, neuronal development, synaptic transmission, and plasticity in brain regions not directly related with the control of reproduction. Central aromatase is also involved in the modulation of cognition, mood, and non-reproductive behaviors. Furthermore, under pathological conditions aromatase is upregulated in the central nervous system. This upregulation represents a neuroprotective and likely also a reparative response by increasing local estradiol levels in order to maintain the homeostasis of the neural tissue. In this paper, we review the non-reproductive functions of neural aromatase and neural-derived estradiol under physiological and pathological conditions. We also consider the existence of sex differences in the role of the enzyme in both contexts.
Topics: Animals; Aromatase; Central Nervous System; Female; Humans; Male; Reproduction; Sex Characteristics
PubMed: 30084008
DOI: 10.1007/s10571-018-0607-4 -
Bioorganic Chemistry Aug 2021Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450... (Review)
Review
Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450 enzyme complex, and play a pivotal role in stimulating cell proliferation. Therefore, deprivation of estrogen by blocking aromatase is considered as the effective way for the inhibition and treatment of breast cancer. In recent years, various non-steroidal heterocyclic functionalities have been extensively developed and studied for their aromatase inhibition activity. This review provides information about the structural-activity relationship of heterocycles (Type II) towards aromatase. This aids the medicinal chemist around the significance of different heterocyclic moieties and helps to design potent aromatase inhibitors.
Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Drug Design; Estrogens; Female; Heterocyclic Compounds; Humans; Structure-Activity Relationship
PubMed: 34091288
DOI: 10.1016/j.bioorg.2021.105017