Increasing CD44+/CD24- tumor stem cells, and upregulation of COX-2 and HDAC6, as major functions of HER2 in breast tumorigenesis

Molecular Cancer

Research

Jau-Nan Lee¹  Hung-Sheng Chen²  Cheng-Yu Long³  Chia-Cheng Chang⁴  Kai-Hung Wang⁵  An-Pei Kao⁵  Eing-Mei Tsai⁶  Ming-Feng Hou⁷ 

[1] Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan;Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, USA;Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;Division of General & Gastroenterological Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;National Sun Yat-Sen University-Kaohsiung Medical University Joint Research Center, Kaohsiung, Kaohsiung, Taiwan;Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan;

关键词: Cancer Stem Cell;    Side Population;    HER2 Expression;    HER2 Overexpression;    Tumor Stem Cell;   

DOI  :  10.1186/1476-4598-9-288

 received in 2010-05-04, accepted in 2010-11-02,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCancer cells are believed to arise primarily from stem cells. CD44+/CD24- have been identified as markers for human breast cancer stem cells. Although, HER2 is a well known breast cancer oncogene, the mechanisms of action of this gene are not completely understood. Previously, we have derived immortal (M13SV1), weakly tumorigenic (M13SV1R2) and highly tumorigenic (M13SV1R2N1) cell lines from a breast epithelial cell type with stem cell phenotypes after successive SV40 large T-antigen transfection, X-ray irradiation and ectopic expression of HER2/C-erbB2/neu. Recently, we found that M13SV1R2 cells became non-tumorigenic after growing in a growth factor/hormone-deprived medium (R2d cells).ResultsIn this study, we developed M13SV1R2N1 under the same growth factor/hormone-deprived condition (R2N1d cells). This provides an opportunity to analyze HER2 effect on gene expression associated with tumorigenesis by comparative study of R2d and R2N1d cells with homogeneous genetic background except HER2 expression. The results reveal distinct characters of R2N1d cells that can be ascribed to HER2: 1) development of fast-growing tumors; 2) high frequency of CD44+/CD24- cells (~50% for R2N1d vs. ~10% for R2d); 3) enhanced expression of COX-2, HDAC6 mediated, respectively, by MAPK and PI3K/Akt pathways, and many genes associated with inflammation, metastasis, and angiogenesis. Furthermore, HER2 expression can be down regulated in non-adhering R2N1d cells. These cells showed longer latent period and lower rate of tumor development compared with adhering cells.ConclusionsHER2 may induce breast cancer by increasing the frequency of tumor stem cells and upregulating the expression of COX-2 and HDAC6 that play pivotal roles in tumor progression.

【 授权许可】

Unknown   
© Wang et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.