RESUMEN
BACKGROUND: Retinoid X Receptor Gamma (RXRG) is a member of the nuclear receptor superfamily and plays a role in tumour suppression. This study aims to explore the prognostic significance of RXRG in breast cancer. METHODS: Primary breast cancer tissue microarrays (n = 923) were immuno-stained for RXRG protein and correlated with clinicopathological features, and patient outcome. RESULTS: Nuclear RXRG expression was significantly associated with smaller tumour size (p = 0.036), lower grade (p < 0.001), lobular histology (p = 0.016), lower Nottingham Prognostic Index (p = 0.04) and longer breast cancer-specific survival (p < 0.001), and longer time to distant metastasis (p = 0.002). RXRG expression showed positive association with oestrogen receptor (ER)-related biomarkers: GATA3, FOXA1, STAT3 and MED7 (all p < 0.001) and a negative correlation with the Ki67 proliferation marker. Multivariate analysis demonstrated RXRG protein as an independent predictor of longer breast cancer-specific survival and distant metastasis-free survival. In the external validation cohorts, RXRG expression was associated with improved patients' outcome (p = 0.025). In ER-positive tumours, high expression of RXRG was associated with better patient outcome regardless of adjuvant systemic therapy. ER signalling pathway was the top predicted master regulator of RXRG protein expression (p = 0.005). CONCLUSION: This study provides evidence for the prognostic value of RXRG in breast cancer particularly the ER-positive tumours.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/metabolismo , Receptor gamma X Retinoide/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Estudios de Cohortes , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Invasividad Neoplásica , Pronóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor gamma X Retinoide/biosíntesis , Receptor gamma X Retinoide/genética , Análisis de Matrices TisularesRESUMEN
PURPOSE: Androgen receptor (AR) and AR signaling pathways are thought to play a role in breast cancer (BC) and are potentially related to treatment responses and outcomes. Ankyrin 3 (ANK3) is associated with AR stability in cancer cells. In the present study, we investigated the clinicopathological utility of ANK3 expression with emphasis on AR and its associated signalling pathway at transcriptomic and proteomic phases. PATIENTS AND METHODS: The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1980) and The Cancer Genome Atlas (TCGA) dataset (n = 1039) were used to assess the expression and significance of ANK3 mRNA and other AR signalling pathway-associated gene signature. Using immunohistochemistry, ANK3 protein expression was evaluated in large (n = 982) cohort of early-stage BC with long-term follow-up and compared with clinicopathological characteristics and its prognostic value in the whole cohort and the subgroups stratified by AR protein expression. RESULTS: An AR-related gene signature was developed, comprising 20 genes, which included ANK3. This AR-related gene signature was significantly associated with AR mRNA expression, oestrogen receptor, human epidermal growth factor receptor 2 (HER2) status and the patients' outcomes. In tumours with high AR protein expression (n = 614), high ANK3 protein expression was significantly associated with progesterone receptor positivity and it was independently associated with the good outcomes (p = 0.025). CONCLUSIONS: This study indicates that ANK3 is related to AR signalling pathway and is associated with BC prognosis.
Asunto(s)
Ancirinas/metabolismo , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Receptores Androgénicos/metabolismo , Ancirinas/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Receptores Androgénicos/genética , Transducción de Señal , Análisis de Supervivencia , Transcriptoma , Carga TumoralRESUMEN
Amikacin is an important antibiotic, and its use is limited because of the induced nephrotoxicity. Thus, search for natural and synthetic agents that can moderate amikacin toxicity never stopped. The present study aims to investigate the possible ameliorative effects of virgin olive oil and olive leaf extract against the amikacin-induced nephrotoxicity in rat. METHODS: 48 rats were distributed into 6 groups: 1-Animals of control (C) group were injected intraperitoneally (ip) with saline, 2-(AK); injected ip with amikacin {300 mg/kg/day for 12days}, 3-(OO) group: given olive oil {7 ml/kg/day for 16days}, 4-(OOAK) group: given olive oil as in OO and amikacin for 12days, 5-(OL) group: given olive leaf extract {50 mg/kg/day for 16days}, 6-(OLAK) group: given leaf extract as in OL and amikacin for 12days. Animals were fasted and sacrificed. Serum was used for biochemical analysis and kidneys for histopathology. RESULTS: Serum urea and creatinine were significantly (P < 0.001) elevated in AK, and significantly dropped in the OOAK and OLAK groups. Serum uric acid was reduced in AK by 45.29%. Kidneys from AK showed necrosis, whereas, those from OOAK and OLAK showed mild histology. The serum triglyceride was decreased by 17.8% in OL, by 37.02% in OOAK and by 31.48% in OLAK. The calculated amikacin effect showed a significant positive correlation with urea (r = 0.521, P = 0.0004), and a negative correlation with uric acid (r = â¿¿ 0.58, P < 0.0001). CONCLUSION: The study confirmed nephrotoxicity of amikacin in rat which was ameliorated by virgin olive oil and by olive leaf extract. Amikacin did not cause dyslipidemia but reduced serum uric acid.