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Breast Cancer Res. 2009;11(6):R79. doi: 10.1186/bcr2446. Epub 2009 Nov 5.

Hes-6, an inhibitor of Hes-1, is regulated by 17beta-estradiol and promotes breast cancer cell proliferation.

Author information

1
Department of Biosciences and Nutrition, Karolinska Institutet, Nobels väg 5, Solna Alfred Nobels Allé 8, 141 57 Huddinge, Sweden. johan.hartman@ki.se

Abstract

INTRODUCTION:

Hes-6 is a member of the basic helix-loop-helix (bHLH) family of transcription factors, and its overexpression has been reported in metastatic cancers 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 also was used to knock down 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 with 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 with 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 downregulation 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 overexpressed 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, could be important for the development of novel anticancer drugs.

PMID:
19891787
PMCID:
PMC2815541
DOI:
10.1186/bcr2446
[Indexed for MEDLINE]
Free PMC Article

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