48PLAT is the core protein involved in physiological plasminogen action in the tissue. PLAT is also involved in cell migration of epithelial/myo-epithelial cells in the human breast.49 In conclusion, our study identified and validated estrogen-regulated genes (NTN4, SLC7A8, ENPP1, MLPH, LAMB2 and PLAT). The reliability of the genes identified in this study was merely reinforced by validation at the mRNA and at protein level. This work provides potential candidates for understanding the pharmacological effects of estrogen and their consequences in estrogen-dependent diseases. We are now studying relevance of these signatures in predicting prognosis/risk classification and would depend upon the use and validation of these signatures in meta-analysis of breast cancer studies. Acknowledgments We thank Dr.

Nilesh M. Dagia for critically reviewing this manuscript. Abbreviations AF-1 activation function 1; AP-1 activation protein 1; ER estrogen receptor; ERE estrogen response element; E2 17��-estradiol; GO gene ontology; PBS phosphate buffer saline; PgR progesterone receptor; RT-qPCR reverse transcription quantitative real-time polymerase chain reaction; TFBS transcription factor binding site; ELF5 E74-like factor 5; E2F1 E2F transcription factor 1; TMA tissue microarray; NFYA nuclear transcription factor Y alpha; AR androgen receptor. Footnotes Disclosures This manuscript has been read and approved by all authors. This paper is unique and is not under consideration by any other publication and has not been published elsewhere. The authors report no conflicts of interest.

Chronic hepatitis C is associated with important morbidity, resulting in liver cirrhosis and its complications in a significant proportion of infected individuals [1]. Due to the rising age of the hepatitis C virus (HCV)-infected population in the Western world, a dramatic increase of cases with advanced liver cirrhosis and hepatocellular carcinoma (HCC) has been predicted for the next decade [1]. Due to the insufficient treatment options for advanced HCC as well as limited number of liver allograft donors for patients with curable disease, improved strategies to screen for early HCC or to prevent the development of HCC are warranted [2]. Recently, two genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the region of DEPDC5 and MICA as susceptibility loci for HCC development in patients with chronic hepatitis C [3], [4]. Although these genetic variations were strongly associated with HCV-induced HCC, with potentially important implications for the identification of patients at AV-951 high risk of developing HCC, it might be challenging to translate these findings into novel therapeutic strategies for HCC.