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    • br Aromatase the key enzyme for estrogen formation in

    2022-11-17


    Aromatase: the key enzyme for estrogen formation in adipose tissue Estrogens are synthesized from androgens by aromatase, a member of the cytochrome P450 superfamily, which is the rate-limiting enzyme in estrogen biosynthesis (Santen et al, 2009, Simpson et al, 1994). At the cellular level, aromatase is localized in the endoplasmic reticulum (Simpson et al., 2002). At the tissue level, the main site of estrogen biosynthesis differs between premenopausal and postmenopausal women. In premenopausal women, estrogens are abundantly produced in the granulosa cells of the ovary with every menstrual cycle, while lower levels of estrogens are also produced in other organs including the bone, adipose tissue, the vascular endothelium, aortic smooth muscle or the Triflusal (Simpson, 2003, Simpson, 2004, Boon et al., 2010). Menopause is characterized by a definitive cessation of ovarian function and extra-gonadal sites then become the main source of estrogens (Misso et al., 2005). Of relevance, excess adipose tissue is believed to be the main site of estrogen production in obese postmenopausal women and contributes to increased circulating estrogen concentrations (Brown and Simpson 2012). Reinforcing the idea that adipose tissue is the major supplier of estrogen in postmenopausal women, studies have shown that estrogen concentrations are linearly associated with BMI and that estrogen formation in fat may be increased by ten-fold in morbidly obese postmenopausal women (Key et al, 2003, Lukanova et al, 2004, van Landeghem et al, 1985, McTiernan et al, 2006, Bezemer et al, 2005, Brown et al, 2017). Adipose tissue is a highly heterogeneous tissue composed of mature adipocytes, pre-adipocytes, fibroblasts, endothelial cells, nerve cells and immune cells (Zhang et al., 2010). Aromatase is primarily expressed in the stromal mesenchymal cells or pre-adipocytes rather than mature adipocytes themselves (Price et al., 1992). These stromal pre-adipocytes are thus a key source of aromatase expression and estrogen production in the breast, and numerous studies have linked them to breast carcinogenesis (Bulun et al, 1993, Bulun et al, 1996). Aromatase expressed in breast adipose stromal cells may have a substantially higher impact on breast carcinogenesis than aromatase expressed in other body sites because of its close proximity to mammary epithelial cells (Bulun et al., 2012). Importantly, in breast cancer cases, the tumor itself has also been found to be a source of aromatase expression and estrogen production, leading to its growth in response to autocrine cues (Lu et al., 1996). Aromatase is encoded by the CYP19A1 gene, located on the short arm of the chromosome 15 (15q21.2) and composed of a 93-kb 5′-untranslated region upstream of the transcription start site, a 30-kb coding region and the 3′-end (Simpson et al, 1994, Simpson et al, 1997, Bulun et al, 2005). The regulation of aromatase transcript expression is a complex process and is controlled in a tissue-specific manner by a number of alternative promoters (Simpson, 2004). So far, ten alternative promoters have been identified in human, including promoters I.1, I.2 and I.2a in placenta, I.4 in adipose tissue, skin and bone, I.5 in fetal tissues, I.f in brain, I.7 in endothelial cells, I.6 in bone, I.3 in adipose tissue and PII in gonads and adipose tissue (Bulun et al, 2005, Bulun et al, 2012, Zhao et al, 2016). Activation of each promoter leads to an alternatively spliced form of mRNA with identical coding regions but distinct first untranslated exons. Therefore, the aromatase protein itself is identical in all expression sites regardless of the promoter used (Zhao et al., 2012). As stated above, each promoter is regulated by a distinct set of transcription factors in a tissue-specific manner. In healthy breast adipose tissue, the relatively weak promoter PI.4 is responsible for the maintenance of low levels of aromatase expression and consequently low levels of estrogen production in the breast, while strong promoters PII and PI.3 remain quiescent (Deb et al., 2006). Promoter PI.4 is under the control of glucocorticoids, class I cytokines (interleukin −6 and −11) and tumor necrosis factor α (TNF-α) (Simpson and Brown, 2013, Macdiarmid et al, 1994). In obesity-related breast cancer, the promoter utilization is different from that of normal breast tissue since more potent promoters II and I.3 are the major promoters activated, leading to increased aromatase expression in this pathological context (To et al., 2015).