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  • In brief while previous studies have


    In brief, while previous studies have evaluated the individual roles of VDR and ER signaling pathways in breast cancer, in the present study we performed an in silico approach for comparative evaluation of these pathways. Considering the complex interaction networks in the context of cancer, such comprehensive approaches are prerequisite for design of novel therapeutic or preventive options for cancer. With the escalating knowledge of the role of lncRNAs in numerous biochemical functions and their involvement in the carcinogenesis process, understanding the specific pathways that are influenced by them and their interactions with TFs especially though in silico analyses will result in development of curative modalities for cancer. Undoubtedly, several challenging issues still persist in this regard. However, the speed of development in this area implies that new innovations are approaching. The final conclusion is that several lncRNAs have regulatory role son both VDR and ESR, so they can influence breast cancer pathogenesis via two important pathways.
    Introduction Phytoestrogens are natural bioactive compounds that may directly or indirectly affect the function of GDC-0152 receptors (Asthana et al., 2014; Stark and Madar, 2002). The structures of active phytoestrogens vary and include types of lignans, coumestans, beta-resorcylic lactones, isoflavonoids or flavonoids that generally share similarities in size and intramolecular spacing (Cassidy, 1999; Slavov and Beger, 2017; Tham et al., 1998). The estrogen receptors, ERα and ERβ, are the focus of this research. ERβ has been called the phytoestrogen receptor and differs from ERα in ligand selectivity, tissue expression and regulation (Hewitt and Korach, 2003; Kuiper et al., 1998; Shanle and Xu, 2011). Estrogen receptor binding assays (ERBA) are used as a tier-1 approach in endocrine disruptor screening, but some of these assays may rely on the use of animals or focus exclusively on ERα (Browne et al., 2015). Assay methods for assessing estrogenic activity may vary in receptor source, choice of ligand, assay volumes, incubation times, endpoint and method of detection. A method using human recombinant estrogen receptors was developed following guidelines by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM/NICEATM, 2003). This study describes the optimization of a bench-top binding assay using ERα and ERβ and estradiol-17β (E2) screening a panel of medicinal herbs. This method has previously been used successfully to assay ginseng, kudzu, mycoestrogens and a rare plant native to the Southeastern United States (Gray et al., 2004, 2016, 2015).
    Materials and methods
    Discussion Several methods are available for detection of estrogenic activity of compounds, including rodent uterine, pS2 induction, cell proliferation, E-SCREEN and reporter gene assays (ICCVAM/NICEATM, 2003; Lackey et al., 2001; Martin et al., 1978; Song et al., 1999; Soto et al., 1995; Zava et al., 1997). These methods require costly and time-consuming maintenance of live animals or cell lines. Additionally, these methods may overlook contributions from crosstalk (see supplemental Fig. S1). The focus of the ERBA presented in this article is on the direct interaction with the ER. This specific focus may be a limitation in some aspects, but was designed to avoid potentially dangerous assumptions that the same response (agonist/antagonist) would be universal in different cell types and organs with different ER expression (see Fig. S1). For example, a chemical may act as an antagonist at classical ERα dimer but display agonist activity at the membrane ER (see Fig. S1). An excellent review on different ER types is provided in (Prossnitz and Arterburn, 2015). Because this assay is cell-free, the functional consequences of post-translational modifications including ER phosphorylation resulting from cross-talk with kinase cascades and receptor turnover from ubiquitination are not assessed. For background on post-translational modifications affecting ER in cells, see (Atsriku et al., 2009).