RESUMEN
Most breast cancer deaths are caused by estrogen receptor-αpositive (ER+) disease. Preclinical progress is hampered by a shortage of therapy-naïve ER+ tumor models that recapitulate metastatic progression and clinically relevant therapy resistance. Human prolactin (hPRL) is a risk factor for primary and metastatic ER+ breast cancer. Because mouse prolactin fails to activate hPRL receptors, we developed a prolactin-humanized Nod-SCID-IL2Rγ (NSG) mouse (NSG-Pro) with physiological hPRL levels. Here, we show that NSG-Pro mice facilitate establishment of therapy-naïve, estrogen-dependent PDX tumors that progress to lethal metastatic disease. Preclinical trials provide first-in-mouse efficacy of pharmacological hPRL suppression on residual ER+ human breast cancer metastases and document divergent biology and drug responsiveness of tumors grown in NSG-Pro versus NSG mice. Oncogenomic analyses of PDX lines in NSG-Pro mice revealed clinically relevant therapy-resistance mechanisms and unexpected, potently actionable vulnerabilities such as DNA-repair aberrations. The NSG-Pro mouse unlocks previously inaccessible precision medicine approaches for ER+ breast cancers.
RESUMEN
OBJECTIVE: Several studies show that chronic opioid dependence leads to higher in-hospital mortality, increased risk of hospital readmissions, and worse outcomes in trauma cases. However, the association of outpatient prescription opioid use on morbidity and mortality has not been adequately evaluated in a critical care setting. The purpose of this study was to determine if there is an association between chronic opioid use and mortality after an ICU admission. DESIGN: A single-center, longitudinal retrospective cohort study of all Intensive Care Unit (ICU) patients admitted to a tertiary-care academic medical center from 2001 to 2012 using the MIMIC-III database. SETTING: Medical Information Mart for Intensive Care III database based in the United States. PATIENTS: Adult patients 18 years and older were included. Exclusion criteria comprised of patients who expired during their hospital stay or presented with overdose; patients with cancer, anoxic brain injury, non-prescription opioid use; or if an accurate medication reconciliation was unable to be obtained. Patients prescribed chronic opioids were compared with those who had not been prescribed opioids in the outpatient setting. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final sample included a total of 22,385 patients, with 2,621 (11.7%) in the opioid group and 19,764 (88.3%) in the control group. After proceeding with bivariate analyses, statistically significant and clinically relevant differences were identified between opioid and non-opioid users in sex, length of hospital stay, and comorbidities. Opioid use was associated with increased mortality in both the 30-day and 1-year windows with a respective odds ratios of 1.81 (95% CI, 1.63-2.01; p<0.001) and 1.88 (95% CI, 1.77-1.99; p<0.001), respectively. CONCLUSIONS: Chronic opioid usage was associated with increased hospital length of stay and increased mortality at both 30 days and 1 year after ICU admission. Knowledge of this will help providers make better choices in patient care and have a more informed risk-benefits discussion when prescribing opioids for chronic usage.
Asunto(s)
Analgésicos Opioides/efectos adversos , Cuidados Críticos/métodos , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Tiempo de Internación , Trastornos Relacionados con Opioides/mortalidad , Centros Médicos Académicos , Estudios de Casos y Controles , Registros Electrónicos de Salud , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Trastornos Relacionados con Opioides/epidemiología , Readmisión del Paciente , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
INTRODUCTION: Emerging evidence in estrogen receptor-positive breast cancer supports the notion that prolactin-Stat5 signaling promotes survival and maintenance of differentiated luminal cells, and loss of nuclear tyrosine phosphorylated Stat5 (Nuc-pYStat5) in clinical breast cancer is associated with increased risk of antiestrogen therapy failure. However, the molecular mechanisms underlying loss of Nuc-pYStat5 in breast cancer remain poorly defined. METHODS: We investigated whether moderate extracellular acidosis of pH 6.5 to 6.9 frequently observed in breast cancer inhibits prolactin-Stat5 signaling, using in vitro and in vivo experimental approaches combined with quantitative immunofluorescence protein analyses to interrogate archival breast cancer specimens. RESULTS: Moderate acidosis at pH 6.8 potently disrupted signaling by receptors for prolactin but not epidermal growth factor, oncostatin M, IGF1, FGF or growth hormone. In breast cancer specimens there was mutually exclusive expression of Nuc-pYStat5 and GLUT1, a glucose transporter upregulated in glycolysis-dependent carcinoma cells and an indirect marker of lactacidosis. Mutually exclusive expression of GLUT1 and Nuc-pYStat5 occurred globally or regionally within tumors, consistent with global or regional acidosis. All prolactin-induced signals and transcripts were suppressed by acidosis, and the acidosis effect was rapid and immediately reversible, supporting a mechanism of acidosis disruption of prolactin binding to receptor. T47D breast cancer xenotransplants in mice displayed variable acidosis (pH 6.5 to 6.9) and tumor regions with elevated GLUT1 displayed resistance to exogenous prolactin despite unaltered levels of prolactin receptors and Stat5. CONCLUSIONS: Moderate extracellular acidosis effectively blocks prolactin signaling in breast cancer. We propose that acidosis-induced prolactin resistance represents a previously unrecognized mechanism by which breast cancer cells may escape homeostatic control.