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    • In ER group Histopathological examination followed

    2021-04-15

    In ER + group, Histopathological examination followed by Fluorescence in situ hybridization (FISH) had revealed the absence of HER2 receptors. Co-targeting of ER and HER2 appears to provide benefit without a significant increase in toxicity although formal trials have not been carried out [18]. Adopting routine ER mutation testing would depend not only on a demonstration of its clinical value in guiding choice of chemotherapy, but on cost and logistical issues as well, including identifying the optimal frequency of testing, taking patient age into account. Liquid biopsy is a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cfDNA and tumor cells, without the spatial and temporal limitations of core biopsies [19]. Early identification of ESR1 mutations by liquid biopsy might allow for timely switching or intensification of chemotherapy through addition of other agents to a compromised endocrine therapy, without need for tissue biopsy and before the emergence of metastatic disease. ddPCR technique is robust for mutation detection in liquid biopsy despite the contamination from white blood cell breakdown leading to suboptimal analysis of cfDNA [21].
    Conclusion
    Funding
    Authors’ contribution
    Conflicts of interest
    Introduction Estrogens are involved in growth and development of reproductive tissues as well as in homeostasis and protection of several non-reproductive organs of the body such as the kidneys [[1], [2], [3]]. The 17β-Estradiol (17βE) is a potent Gliotoxin that participates in regulation of different physiological mechanisms including cell proliferation, adhesion, migration, and morphogenesis [[4], [5], [6]]. The physiological effects of estrogen are traditionally mediated by the classic estrogen receptors (ER) ERα and ERβ, which are members of the nuclear receptor superfamily [5]. Estrogen binding to the ERs results in conformational changes that promote the monomeric receptor to dimerize and transfer to the nucleus where it recognizes distinct DNA sequences in the promoter regions of target genes [7,8]. Both ERα and ERβ are expressed in the kidneys of mice and rats [9,10]. ERα and ERβ are localized mainly to the mouse renal proximal tubules and to a lesser extent in distal nephron segments [9]. Estrogens also exert their effects by binding to the G protein-coupled estrogen receptor 1 (GPER-1) also known as G protein-coupled receptor 30 (GPR30) [[11], [12], [13]]. Several reports have suggested that estrogen, through the activation of GPER-1, can also mediate cellular functions including growth, cell proliferation, and apoptosis [14,15]. GPER-1 is expressed in the mouse kidney and localized to the epithelial cells of the proximal and distal convoluted tubules, and the loop of Henle [3]. Most studies investigating the intracellular mechanisms of the protective effects of estradiol were conducted in reproductive tissues, cancer cell lines, and genetically modified cell lines [4,5,7,8,13,[15], [16], [17]]. In ovarian cancer cells, the transcriptional activation of known estrogen-responsive genes occurs through GPER-1 as well as ERα, possibly using a common intracellular pathway [17]. Moreover, during the proliferative phase of the menstrual cycle, estrogen induces proliferation in the endometrium through modulating the Wnt/β-catenin pathway [18]. Accumulation of β-catenin, can activate signaling processes controlling cell proliferation. Active cytosolic β-catenin is able to translocate to the nucleus and associates with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors, allowing the transcription and upregulation of target genes, thereby inducing cell proliferation [19,20]. There are a few studies reporting the effect of estradiol on renal cell proliferation in animal models [21,22], however, the direct effect of estradiol on cell proliferation as well as the expression and intracellular signaling pathways of estrogen receptors has not been studied in the tubular epithelium of the human kidney. The renal tubular epithelium is almost mitotically inactive, and most of the epithelial cells remain quiescent but after stimulation or injury, the renal tubules acquire the ability to regenerate, a process in which cell proliferation constitutes one of the main steps [23,24]. Whether estradiol participates in the renal tubular regeneration process by modulating the cell proliferation remains to be investigated. Therefore, the aim of the present work was to study the effect of 17βE on cell proliferation in the human renal tubular epithelium, and the involvement of the classical estrogen receptors as well as the GPER-1 on this effect. For this purpose, we used primary cultures of human renal tubular epithelial cells (HRTEC) from pediatric subjects as a model of the human proximal tubule [25] based on its ability to preserve the physiological and structural properties of the original renal epithelium [26]. Furthermore, the role of β-catenin on HRTEC proliferation regulated by estradiol was also analyzed.