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Receptors, Volume 4, Issue 2 (June 2025) – 3 articles

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16 pages, 3466 KiB  
Article
Gelsolin Facilitates Estrogen Receptor Beta Nuclear Translocation and Transcriptional Repression of Genes Associated with Alzheimer Disease
by Yoldas Yildiz, Angela H. S. Fan, Amanda A. Hartoun, Sarah Flury, Yan Ngai and Toni R. Pak
Receptors 2025, 4(2), 10; https://doi.org/10.3390/receptors4020010 - 1 May 2025
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Abstract
Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost [...] Read more.
Background/Objectives: Gelsolin (GSN) is an actin-binding protein that helps maintain neuronal structure and shape, regulates neuronal growth, and apoptosis. Our previous work demonstrated that GSN associated with estrogen receptor beta (ERβ1) in the brains of female rats, but this association was lost in advanced age. GSN was also required for ERβ1-mediated transcriptional repression at activator protein-1 (AP-1) motifs upstream of a minimal gene promoter. However, the consequences of the loss of GSN:ERβ1 protein interaction on ERβ1 nuclear translocation and transcriptional repression at AP-1 sites located within complex endogenous gene promoters remained unclear. Methods: We used immunofluorescent super resolution microscopy and luciferase reporter assays to test the hypothesis that GSN facilitates ERβ1 nuclear translocation and transcriptional repression of two genes relevant for Alzheimer Disease: APP (amyloid-beta precursor protein) and ITPKB (inositol-1,4,5-trisphosphate 3-kinase B). Results: Our results revealed the novel finding that GSN is required for ERβ1 ligand-independent nuclear translocation in neuronal cells. Moreover, we show that GSN increased APP and ITPKB promoter activity, which was repressed by ERβ1. Conclusions: Together, these data revealed the importance of the cytoskeletal protein, GSN, in regulating intracellular trafficking of nuclear receptors and demonstrate the first evidence of ERβ1 directly regulating two genes that are implicated in the progression of AD. Full article
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19 pages, 1670 KiB  
Review
Bioelectric Membrane Potential and Breast Cancer: Advances in Neuroreceptor Pharmacology for Targeted Therapeutic Strategies
by Chitaranjan Mahapatra, Jineetkumar Gawad, Chandrakant Bonde and Mahesh B. Palkar
Receptors 2025, 4(2), 9; https://doi.org/10.3390/receptors4020009 - 2 Apr 2025
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Abstract
Bioelectric membrane potentials regulate cellular growth, differentiation, and movement. Disruptions in bioelectric signaling are strongly linked to cancer development, as abnormal membrane potentials and ion channel activity can drive tumor progression. In breast cancer, ion channel dysfunction and neuroreceptor-related pathways play significant roles [...] Read more.
Bioelectric membrane potentials regulate cellular growth, differentiation, and movement. Disruptions in bioelectric signaling are strongly linked to cancer development, as abnormal membrane potentials and ion channel activity can drive tumor progression. In breast cancer, ion channel dysfunction and neuroreceptor-related pathways play significant roles in the cell cycle, epithelial–mesenchymal transition, angiogenesis, inflammation, the tumor microenvironment, and tumor progression. Neuroreceptors are critical not only in initiating and advancing cancer but also in conferring resistance to treatments. Neuroreceptors also play a key role, with dopamine receptor D2 activation reducing breast tumor growth by 40% in preclinical models, while serotonin signaling has been shown to promote epithelial–mesenchymal transition (EMT), increasing invasiveness. Advances in understanding these biological mechanisms could lead to more cost-effective and less invasive therapeutic strategies to treat tumors. This review explores the expanding evidence connecting bioelectric activity to breast cancer, focusing on neuroreceptor pharmacology as a transformative therapeutic approach. Examining the modulation of bioelectricity through neuroreceptor pharmacology to influence breast cancer progression and integrating these insights into therapeutic development offers a promising path for addressing treatment challenges and improving precision in managing aggressive cancer subtypes. Full article
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9 pages, 934 KiB  
Perspective
Role of Glucocorticoid Receptor in Triple-Negative Breast Cancer
by Raj Kumar
Receptors 2025, 4(2), 8; https://doi.org/10.3390/receptors4020008 - 1 Apr 2025
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Abstract
Triple-negative breast cancer (TNBC) is an aggressive tumor among breast cancer subtypes with much lower overall survival at metastasis compared to other subtypes and with limited treatment options due to a lack of targeted therapies. This has led to the investigation of molecular [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive tumor among breast cancer subtypes with much lower overall survival at metastasis compared to other subtypes and with limited treatment options due to a lack of targeted therapies. This has led to the investigation of molecular targets to advance the development of novel therapeutic agents aimed at treating TNBC patients. Recent studies have led us to believe that glucocorticoid receptor (GR) expression may be predictive of decreased survival and increased risk of metastasis in TNBC tumors. Thus, a detailed understanding of GR signaling in TNBC may help understand the role of GR in TNBC proliferation as well as its role as a potential biomarker and therapeutic target. Recent research findings indicate that GR-induced gene regulations may provide an important platform for the development of GR-based therapeutic targets in TNBC. Emerging data from laboratories indicate that targeting GR has the potential to inhibit cancer cell proliferation and reduce tumor growth in TNBC. Therefore, future research focused on underlying molecular mechanisms of GR action in TNBC could lead to a new effective treatment option for TNBC patients, which is urgently needed. Full article
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