RESUMEN
Estrogen is an important hormone for health in both genders. It is indispensable to glucose homeostasis, immune robustness, bone health, cardiovascular health, and neural functions. The main way that estrogen acts in the cells is through estrogen receptors (ERs). The presence of specific estrogen receptors is required for estrogen to have its characteristic ubiquitous action in almost all tissues. Estrogen receptor alpha (ERα) and estrogen receptor beta (ERß) are the major isoforms of estrogen that are highly specific in humans and enable selective hormonal actions in different tissues. This article reviews some of the observed estrogen actions and effects in different tissues and cells through these specific receptors. This ubiquitous, almost ordinary hormone may reveal itself as a significant factor that helped us to better understand the complexity of the human immune system response against respiratory infections, including the COVID-19, and especially in the current state of this painful pandemic.
Asunto(s)
COVID-19/inmunología , Receptor alfa de Estrógeno/inmunología , Receptor beta de Estrógeno/inmunología , Sistema Inmunológico/inmunología , Sistema Respiratorio/inmunología , SARS-CoV-2/inmunología , Animales , COVID-19/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Mucosa Nasal/inmunología , Mucosa Nasal/metabolismo , Sistema Respiratorio/metabolismo , SARS-CoV-2/metabolismoRESUMEN
Inflammation has been recently acknowledged as a key participant in the physiopathology of oncogenesis and tumor progression. The inflammatory cytokine IL-1ß has been reported to induce the expression of markers associated with malignancy in breast cancerous cells through Epithelial-Mesenchymal Transition (EMT). Aggressive breast cancer tumors classified as Triple Negative do not respond to hormonal treatment because they lack three crucial receptors, one of which is the estrogen receptor alpha (ERα). Expression of ERα is then considered a good prognostic marker for tamoxifen treatment of this type of cancer, as the binding of this drug to the receptor blocks the transcriptional activity of the latter. Although it has been suggested that inflammatory cytokines in the tumor microenvironment could regulate ERα expression, the mechanism(s) involved in this process have not yet been established. We show here that, in a cell model of breast cancer cells (6D cells), in which the inflammatory cytokine IL-1ß induces EMT by activation of the IL-1ß/IL-1RI/ß-catenin pathway, the up regulation of TWIST1 leads to methylation of the ESR1 gene promoter. This epigenetic modification produced significant decrease of the ERα receptor levels and increased resistance to tamoxifen. The direct participation of IL-1ß in these processes was validated by blockage of the cytokine-induced signaling pathway by wortmannin inactivation of the effectors PI3K/AKT. These results support our previous reports that have suggested direct participation of the inflammatory cytokine IL-1ß in the transition to malignancy of breast cancer cells.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Metilación de ADN , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/genética , Interleucina-1beta/inmunología , Tamoxifeno/farmacología , Mama/efectos de los fármacos , Mama/inmunología , Mama/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Metilación de ADN/efectos de los fármacos , Receptor alfa de Estrógeno/inmunología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Células MCF-7 , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Fosfatidilinositol 3-Quinasas/inmunología , Regiones Promotoras Genéticas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/inmunologíaRESUMEN
In the present study, we aimed to evaluate estrogen receptor ER-alpha status in 61 breast cancer cases using Sp1 and 1D5 monoclonal antibodies. Tissue array platforms were generated containing samples of breast cancer and positive controls that were assayed by immunohistochemistry applying monoclonal primary antibodies anti-ER alpha, SP1 and 1D5. We noted a high concordance rate (96.7%) between the referred antibodies. Moreover, we calculated the Kappa factor (0.921), indicating that 1D5 and SP1 provided overlapping ERα expression results. Indeed, we observed controversial results only in 2 samples studied, which were ER-negative when stained with 1D5 and ER-positive when assessed with SP1. Total concordance of PS was obtained (Pearson and intraclass CF, 0.7351 and 0.6193, respectively). However, concordance between the antibodies seems to be more accurate in higher PS values. An excellent IS correlation between antibodies was observed throughout the population (Spearman's CF, ρ=0.9150). Following the Allred score, 17 out of 42 positive BC samples diverged, with 1D5 always pointing to weaker staining than SP1. When calculating Spearman's CF of Total Score (TS) within the population, an excellent correlation between both the antibodies (ρ=0.9238) was noted. Nonetheless, the results were less concordant among the BC-positive cases (ρ=0.7743). Indeed, 20 samples were differentially classified using the antibodies (only 3 had higher TS with 1D5). Considering the mean TS of all samples or of invasive ductal carcinoma, SP1 provided higher scores than 1D5 (p<0.05). We recommend the use of the anti-ER RMAb SP1 due to the high probability that the BC ERα status can be determined accurately as the reagent provides higher IS. Therefore, the A-score was higher than the MMAb 1D5. Ultimately, higher IS and A-score decrease the possibility of ERα status misinterpretation and, consequently, inappropriate BC treatment that would compromise the patient's quality of life and overall survival. We recommend the use of anti-ER RMAb SP1 due to the high probability that the BC ER status can be determined accurately as the reagent provides higher IS, therefore higher A-score, than the MMAb 1D5.
Asunto(s)
Adenocarcinoma/diagnóstico , Anticuerpos Monoclonales , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/diagnóstico , Receptor alfa de Estrógeno/inmunología , Femenino , Humanos , Inmunohistoquímica/métodos , Reproducibilidad de los Resultados , Análisis de Matrices TisularesRESUMEN
Long-term formalin tissue fixation results in antigen masking, probably through aldehydic linkage between proteins and fixative molecules. Immunohistochemistry results depend on the type of the detection procedure and the type of antibody used for the reaction. Considering the difficulty in working with estrogen receptor (ER) antibodies and the lack of standardization of the antigen retrieval methods, we quantified the immunoexpression of ER using the 1D5 antibody and a standard streptavidin-biotin detection procedure retrieving with microwave oven, steamer, pressure cooker, and water bath in a set of SBR grade 2 invasive breast carcinomas. Pressure-cooking provided the best results. No significant differences were observed in using the other methods. Pressure-cooking should be recommended as the method of choice for standardization of the ER immunohistochemical reaction.