Re: Hes-6, potential oncogene in bc, is regulated by ER and promotes proliferation
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Breast Cancer Res. 2009 Nov 5;11(6):R79. [Epub ahead of print] Hes-6, an inhibitor of Hes-1, is regulated by 17beta-estradiol and promotes breast cancer cell proliferation.
Hartman J, Lam EW, Gustafsson JA, Strom A.
ABSTRACT: INTRODUCTION: Hes-6 is a member of the basic-helix-loop-helix (bHLH) family of transcription factors and its over expression has been reported in metastatic cancer of different origins. Hes-6 has been described as an inhibitor of Hes-1 during neuronal development, although its function in cancer is not known. In this study, we investigated the function of Hes-6 in breast cancer and tested the hypothesis that Hes-6 enhances breast cancer cell proliferation and is regulated by estrogen. METHODS: To investigate the function of Hes-6, T47D cells stably expressing Hes-6 were generated by lentiviral transduction and, conversely, siRNA was also used to knockdown Hes-6 expression in breast cancer cells. The Hes-6 expressing T47D cells were transplanted into immunodeficient mice to study effects on tumor growth. RESULTS: We found that Hes-6 expression was significantly higher in the high-grade, estrogen receptor (ER)alpha-negative SKBR3 and MDA-MB-231 cells compared to the ERalpha-positive, non-metastasizing T47D and MCF-7 breast carcinoma cells. Moreover, the level of Hes-6 mRNA was 28 times higher in breast cancer samples compared to normal breast samples. In Hes-6 expressing T47D cells, Hes-6 ectopic expression was shown to stimulate cell proliferation in vitro as well as breast tumor growth in xenografts. Moreover, expression of Hes-6 resulted in induction of E2F-1, a crucial target gene for the transcriptional repressor Hes-1. Consistently, silencing of Hes-6 by siRNA resulted in down-regulation of E2F-1 expression, whereas estrogen treatment caused induction of Hes-6 and downstream targets hASH-1 and E2F-1 in MCF-7 cells. CONCLUSIONS: Together the data suggest that Hes-6 is a potential oncogene over expressed in breast cancer, with a tumor promoting and proliferative function. Furthermore, Hes-6 is a novel estrogen regulated gene in breast cancer cells. An understanding of the role and regulation of Hes-6 could provide insights into estrogen signaling and endocrine resistance in breast cancer and, hence, be important for the development of novel anticancer drugs.
PMID: 19891787 [PubMed - as supplied by publisher]
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