Estrogen receptor alpha-encoded by ESR1 gene-overexpression correlates with prognosis and response to specific chemotherapy in breast adenocarcinoma cases. Mechanisms of ESR-1 deregulation in carcinomas remain under investigation. To analyze ESR1 in carcinomas of different histogenesis. Using tissue microarray technology, 172 primary carcinomas including breast ductal adenocarcinomas (n=60), hepatocellular carcinomas (n=52), and colon adenocarcinomas (n=60) were cored and re-embedded in three paraffin blocks. Initial diagnosis was based on liquid based cytology (LiquiPrep/ThinPrep). Immunohistochemistry and fluorescence in situ hybridization were performed. Quantitative evaluation of ER-a protein levels was assessed by applying digital image analysis. ER-a overexpression was observed in 41/60 (68.3%), 23/52 (44.2%) and 4/60 (6.6%) cases, respectively. ESR1 gene multiple copies were confirmed in 13/60 (21.6%) breast adenocarcinomas, but high amplification only in 8/13 (62.8%). Allelic absence was identified in 3/52 (5.7%) hepatocellular carcinomas, whereas colon adenocarcinomas demonstrated gene gains in 5/60 (8.3%) cases referred to chr 6 aneuploidy and not to amplification. ER-a overall expression was associated strongly to ESR1 gene copies only in breast carcinoma (P=0.036). ESR-1 gene overexpression happens frequently in breast cancer, but only a subset of them are high amplified cases correlated to increased response rates in hormonal therapy (tamoxifen). Absence of this mechanism in hepatocellular and colon carcinomas maybe is a negative factor for applying this therapy. This is a pattern of histo-genetic depended targeted therapeutic strategy.