RESUMEN
OBJECTIVE: To evaluate whether a single preoperative dose of tamsulosin reduces the time to postoperative void and time to discharge in patients who are undergoing minimally invasive hysterectomy. METHODS: This single-center, block-randomized, placebo-controlled, double-blind superiority trial evaluated the effect of 0.4 mg tamsulosin compared with placebo on the time to void after hysterectomy. Patients who underwent outpatient minimally invasive hysterectomy were randomized to a single dose of tamsulosin or placebo 1 hour before surgery. All participants underwent a standardized backfill void trial to eliminate discrepancies in bladder volume that would otherwise affect the time to void. For our primary aim, we planned to enroll 150 participants to show a 30-minute reduction in the time to postoperative void (80% power, α<0.05). The secondary aim was to compare the time to discharge from the postanesthesia care unit. RESULTS: From June 2021 through January 2023, 344 patients were screened, and 150 were included in the final data analysis: 77 in the tamsulosin group and 73 in the placebo group. The time to spontaneous void was not different between the tamsulosin and placebo groups (106 minutes vs 100 minutes, P=.5). In addition, there was no statistical difference in time to discharge from the postanesthesia care unit (144 minutes vs 156 minutes, P=.4). Demographics and surgical details were not different between each group. CONCLUSION: A single dose of tamsulosin preoperatively does not lead to a decrease in postoperative time to void or time to discharge in patients undergoing minimally invasive hysterectomy for benign conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04859660.
RESUMEN
Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for ß-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for ß-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on ß-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC. SIGNIFICANCE: These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/5/982/F1.large.jpg.
Asunto(s)
Proteínas Proto-Oncogénicas/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Proteínas Wnt/metabolismo , Acetilación , Alelos , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Biomarcadores de Tumor , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Proteína Potenciadora del Homólogo Zeste 2/biosíntesis , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Femenino , Proteína HMGA2/biosíntesis , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Factor de Unión 1 al Potenciador Linfoide , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Metástasis de la Neoplasia , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacología , Tasa de Supervivencia , Factor de Transcripción 4 , Neoplasias de la Mama Triple Negativas/genética , beta Catenina/metabolismoRESUMEN
A body of epidemiological evidence implicates exposure to endocrine disrupting chemicals (EDCs) with increased susceptibility to breast cancer. To evaluate the physiological effects of a suspected EDC in vivo, we exposed MCF-7 breast cancer cells and a patient-derived xenograft (PDX, estrogen receptor positive) to physiological levels of methylparaben (mePB), which is commonly used in personal care products as a preservative. mePB pellets (4.4 µg per day) led to increased tumor size of MCF-7 xenografts and ER+ PDX tumors. mePB has been thought to be a xenoestrogen; however, in vitro exposure of 10 nM mePB failed to increase MCF-7 cell proliferation or induction of canonical estrogen-responsive genes (pS2 and progesterone receptor), in contrast to 17ß-estradiol (E2) treatment. MCF-7 and PDX-derived mammospheres exhibited increased size and up-regulation of canonical stem cell markers ALDH1, NANOG, OCT4 and SOX2 when exposed to mePB; these effects were not observed for MDA-MB-231 (ER- ) mammospheres. As tumor-initiating cells (TICs) are also believed to be responsible for chemoresistance, mammospheres were treated with either tamoxifen or the pure anti-estrogen fulvestrant in the presence of mePB. Blocking the estrogenic response was not sufficient to block NANOG expression in mammospheres, pointing to a non-classic estrogen response or an ER-independent mechanism of mePB promotion of mammosphere activity. Overall, these results suggest that mePB increases breast cancer tumor proliferation through enhanced TIC activity, in part via regulation of NANOG, and that mePB may play a direct role in chemoresistance by modulating stem cell activity. Copyright © 2016 John Wiley & Sons, Ltd.
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Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/genética , Carcinógenos/toxicidad , Disruptores Endocrinos/toxicidad , Células Madre Neoplásicas/efectos de los fármacos , Parabenos/toxicidad , Receptores de Estrógenos/genética , Animales , Carcinógenos/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Estradiol/farmacología , Antagonistas de Estrógenos/farmacología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , Proteínas de Neoplasias/genética , Ovariectomía , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Osteoporosis is a disease characterized by low bone mass, leading to an increased risk of fragility fractures. GATA4 is a zinc-finger transcription factor that is important in several tissues, such as the heart and intestines, and has recently been shown to be a pioneer factor for estrogen receptor alpha (ERα) in osteoblast-like cells. Herein, we demonstrate that GATA4 is necessary for estrogen-mediated transcription and estrogen-independent mineralization in vitro. In vivo deletion of GATA4, driven by Cre-recombinase in osteoblasts, results in perinatal lethality, decreased trabecular bone properties, and abnormal bone development. Microarray analysis revealed GATA4 suppression of TGFß signaling, necessary for osteoblast progenitor maintenance, and concomitant activation of BMP signaling, necessary for mineralization. Indeed, pSMAD1/5/8 signaling, downstream of BMP signaling, is decreased in the trabecular region of conditional knockout femurs, and pSMAD2/3, downstream of TGFß signaling, is increased in the same region. Together, these experiments demonstrate the necessity of GATA4 in osteoblasts. Understanding the role of GATA4 to regulate the tissue specificity of estrogen-mediated osteoblast gene regulation and estrogen-independent bone differentiation may help to develop therapies for postmenopausal osteoporosis.
Asunto(s)
Proteínas Morfogenéticas Óseas/metabolismo , Receptor alfa de Estrógeno/metabolismo , Factor de Transcripción GATA4/metabolismo , Osteoblastos/metabolismo , Osteogénesis/fisiología , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Proteínas Morfogenéticas Óseas/genética , Diferenciación Celular/fisiología , Células Cultivadas , Receptor alfa de Estrógeno/genética , Factor de Transcripción GATA4/genética , Regulación de la Expresión Génica/fisiología , Ratones , Ratones Transgénicos , Osteoblastos/citología , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Wnt/ß-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of ß-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active ß-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours. We provide evidence that transgenic murine Wnt10b-driven tumours are devoid of ERα, PR and HER2 expression and can model human TNBC. Importantly, HMGA2 is specifically expressed during early stages of embryonic mammogenesis and absent when WNT10B expression is lost, suggesting a developmentally conserved mode of action. Mechanistically, ChIP analysis uncovered that WNT10B activates canonical ß-catenin signalling leading to up-regulation of HMGA2. Treatment of mouse and human triple-negative tumour cells with two Wnt/ß-catenin pathway modulators or siRNA to HMGA2 decreases HMGA2 levels and proliferation. We demonstrate that WNT10B has epistatic activity on HMGA2, which is necessary and sufficient for proliferation of TNBC cells. Furthermore, HMGA2 expression predicts relapse-free-survival and metastasis in TNBC patients.