Molecular Pathways of Estrogen Receptor Action

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In addition to cancerous cells, the non-cancer cells including tumor microenvironment (TME) are critical mediators of tumor progression. Besides the intracellular signaling, the interactions between cancer cells, stromal cells, immune cells, and extracellular molecules within the TME greatly impact antitumor immunity and the immunotherapeutic response. The potential role of estrogen signaling pathway, as a regulator of tumor immune responses, in the tumor microenvironment is discussed and reviewed by Rothenberger et al. [6]. Radiation therapy is widely used as one of the most common and effective therapeutic strategies. Nevertheless, the effect of ionizing radiation on the expression of ERs and ER signaling pathways in cancerous tissues, as well as on the endocrine therapy is not well-known. This topic is reviewed and discussed by Rong et al. [7]. They also summarize basic, pre-clinical and clinical studies that assess the consequences of anti-estrogen treatments in combination with radiotherapy in cancer.
There is an important link between estrogen signaling pathways and the regulation of the cardiovascular and immune systems. Trenti et al. [8] review the current understanding of the protective effects of estrogen on the cardiovascular system, including promoting endothelial healing and angiogenesis. They also describe the actions of estrogens in the immune function of the monocyte-macrophage system, through different pathways and in particular with regard to the production of cytokines. Recent studies have also suggested that estrogens exert their vascular protective effects, at least in part, through microRNA activity. Pérez-Cremades et al. [9] focus on the recent progress in determining the roles of estrogen-regulated microRNAs and their contribution in vascular biology. They summarize the microRNAs involved in estrogen action and the major role played by miR-23a and miR-22. However, further works focused on characterizing the role of estradiol-mediated miRNAs involved in vascular function are needed. Wnuk and Kajta [10] highlight the role of steroid and xenobiotic receptor signaling in apoptosis and autophagy of the central nervous system, and their potential implications in brain diseases. Finally, Lecomte et al. [11] discuss and summarize the in vitro and in vivo effects of phytochemicals interacting with ERs and their potential role in human health. The diversity of the mechanisms of action and the subtle balance between beneficial and harmful biological outcomes are also given.
In addition to the reviews mentioned above, eight research articles are included in this special issue. A clinical study reported by Matta et al. [12] describes a substantial variability in DNA repair capacity among breast cancer subtypes and suggests lowest repairs in triple negative breast cancer. Cardoso et al. [13] report estrogen metabolism-associated CYP2D6 and IL6-174G/C polymorphisms in Schistosoma haematobium Infection. From a primary culture approach, Kranc et al. [14] analyze the expression profile of genes regulating steroid biosynthesis and metabolism in human ovarian granulosa cells. An in vivo study conducted by d'Adesky et al. [15] indicates that nicotine modifies ER-β-regulated inflammasome activity and aggravates ischemic brain damage in female rats. The study conducted by Casanova-Nakayama et al. [16] examines the immune-specific expression and estrogenic regulation of the four ER isoforms in female rainbow trout. Alexandre-Pires et al. [17] evaluate functional aspects of sheep inguinal sinus gland and the mRNA and protein expressions of several hormone receptors including ERs. An in vivo and in vitro study conducted by Hinfray et al. [18] provides evidence regarding antagonistic effects of estradiol and genistein in combination using mixture concentration-response modeling in zebrafish. Serra et al. [19] report that triclosan lacks (anti-)estrogenic effects in zebrafish cells but alters estrogen response in zebrafish embryos.
While much remains to be learned, this special issue provides a background of the molecular mechanisms of ERs that is needed in clinical studies against estrogen-related diseases. Lastly, I would like to thank all the authors and referees for their efforts in supporting this special issue.

Conflicts of Interest:
The author declares no conflict of interest.