2099

ESR1

ER|ESR|ESRA|ESTRR|Era|NR3A1;estrogen receptor 1;ESR1;estrogen receptor 1

ER-alpha|estradiol receptor|estrogen nuclear receptor alpha|estrogen receptor|estrogen receptor alpha E1-E2-1-2|estrogen receptor alpha E1-N2-E2-1-2|nuclear receptor subfamily 3 group A member 1

6q25.1

protein-coding

Estrogen receptor alpha (ERalpha) is present in about 70 % of human breast cancers and, working in conjunction with extracellular signal-regulated kinase 2 (ERK2), this nuclear hormone receptor regulates the expression of many protein-encoding genes. Given the crucial roles of miRNAs in cancer biology, we investigated the regulation of miRNAs by estradiol (E2) through ERalpha and ERK2, and their impact on target gene expression and phenotypic properties of breast cancer cells. We identified miRNA-encoding genes harboring overlapping ERalpha and ERK chromatin binding sites in ERalpha-positive MCF-7 cells and showed ERalpha and ERK2 to bind to these sites and to be required for transcriptional induction of these miRNAs by E2. Hsa-miR-196a2*, the most highly estrogen up-regulated miRNA, markedly down-regulated tumor protein p63 (TP63), a member of the p53 family. In ERalpha-positive and ERalpha-negative breast cancer cells, proliferative and invasiveness properties were suppressed by hsa-miR-196a2* expression and enhanced by hsa-miR-196a2* antagonism or TP63 target protector oligonucleotides. Hsa-miR-196a2* and TP63 were inversely correlated in breast cancer cell lines and in a large cohort of human breast tumors, implying clinical relevance. The findings reveal a tumor suppressive role of hsa-miR-196a2* through regulation of TP63 by ERalpha and/or ERK2 signaling. Manipulating the hsa-miR-196a2*-TP63 axis might provide a potential tumor-suppressive strategy to alleviate the aggressive behavior and poor prognosis of some ERalpha-positive as well as many ERalpha-negative breast cancers.

Hepatocellular carcinoma (HCC) is one of the top five causes of cancer-related deaths worldwide. Recent developments in the treatment of HCC remain insufficient to cure unresectable disease or to prevent HCC. Consistent efforts are, therefore, needed to deepen understanding of pathogenesis of the disease. Genome-wide gene expression profile analyses can now detect various candidate genes that are modified by HCC. We have developed a new technique to identify tumor suppressor genes, triple-combination array analysis, which combines gene expression profiles, single nucleotide polymorphism and methylation arrays to identify genes with altered expression. Using HCC tissue samples, triple-combination array analysis was performed to identify a candidate tumor suppressor gene. Subsequently, samples from 48 HCC patients were subjected to quantitative polymerase chain reaction (qPCR) and methylation-specific PCR to further elucidate clinical relevance of the gene. Estrogen receptor 1 (ESR1) was detected as a candidate tumor suppressor gene. Of the 48 clinical samples, 40 (83.3%) showed ESR1 promoter hypermethylation. In 24 (50%) HCC samples, the expression levels of the ESR1 gene was decreased by >90%. The decreased expression was significantly related to high liver damage score, pathological invasion of the intrahepatic portal vein, the size of tumor (>3 cm in diameter) and hepatitis B virus infection. The present study represents another example that triple-combination array is a convenient technique for detecting genes with altered expression in disease. The ESR1 gene was identified as a candidate tumor suppressor gene in HCC and further validation is warranted.