RESUMEN
Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in human cancers due to mutation, amplification, and epigenetic hyperactivity, which leads to deregulated transcriptional mechanism. Among the eight different EGFR isoforms, the mechanism of regulation of full-length variant 1 is well-known, no studies have examined the function & factors regulating the expression of variant 8. This study aimed to understand the function of EGFR super-enhancer loci and its associated transcription factors regulating the expression of EGFR variant 8. Our study shows that overexpression of variant 8 and its transcription was more prevalent than variant 1 in many cancers and positively correlated with the EGFR-AS1 expression in oral cancer and HNSCC. Notably, individuals overexpressing variant 8 showed shorter overall survival and had a greater connection with other clinical traits than patients with overexpression of variant 1. In this study, TCGA enhancer RNA profiling on the constituent enhancer (CE1 and CE2) region revealed that the multiple enhancer RNAs formed from CE2 by employing CE1 as a promoter. Our bioinformatic analysis further supports the enrichment of enhancer RNA specific chromatin marks H3K27ac, H3K4me1, POL2 and H2AZ on CE2. GeneHancer and 3D chromatin capture analysis showed clustered interactions between CE1, CE2 loci and this interaction may regulates expression of both EGFR-eRNA and variant 8. Moreover, increased expression of SNAI2 and its close relationship to EGFR-AS1 and variant 8 suggest that SNAI2 could regulates variant 8 overexpression by building a MegaTrans complex with both EGFR-eRNA and EGFR-AS1. Our findings show that EGFR variant 8 and its transcriptional regulation & chromatin modification by eRNAs may provide a rationale for targeting RNA splicing in combination with targeted EGFR therapies in cancer.
Asunto(s)
ARN Potenciadores , Neoplasias de Cabeza y Cuello , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Súper Potenciadores , Receptores ErbB/genética , Cromatina/genética , Neoplasias de Cabeza y Cuello/genéticaRESUMEN
PURPOSE: The objective of this study was to assess response to neoadjuvant chemotherapy in molecular subtypes of breast cancer. METHODS: This study included 60 patients with locally advanced and metastatic breast cancer. The authors excluded patients who already underwent mastectomy or were given any chemotherapy/radiotherapy. They analyzed the clinical and immunohistochemical characteristics using core biopsy specimens to determine their correlations with response to chemotherapy. RESULTS: A clinical complete response was observed in 19 patients (31.7%), a clinical partial response in 30 patients (50%), clinical stable disease in 8 patients (13.3%), and progressive disease in 3 patients (5%). A pathologic complete response (pCR) was observed in 7 (21.87%) of 32 patients who underwent surgery. High Ki-67 was associated with human epidermal growth factor receptor 2 (HER2)-positive status (P = 0.027) and triple-negative breast cancer (TNBC) (P = 0.006). Multiple logistic regression analysis showed that pCR was correlated with HER2 status (odds ratio 26.589, confidence interval [CI] =1.606-44.190), P = 0.022. Of the seven patients found to have pCR, six patients (85.7%) were treated with taxol-containing regimen. The other parameters that were correlated with pCR are TNBC and estrogen receptor/progesterone receptor status. Tumor size, Ki-67 value, and grade of the tumor were not correlated with clinical response. CONCLUSION: Molecular subtype in breast cancer is an effective factor for predicting response to neoadjuvant chemotherapy. HER2-positive status was associated with high Ki-67 and high clinical and pathological response rate. Taxol needs to be added in neoadjuvant chemotherapy to improve pCR. Luminal subtypes respond poorly to chemotherapy.