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Department of Biological Sciences


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Hexin Chen


Department of Biology
University of South Carolina

Office: PSC621
Phone Number: 803-777-2928
Email: chen53@mailbox.sc.edu
Website: Chen Lab Homepage
Photo of Dr. Chen

Despite aggressive clinical treatments which include surgical resection, radiation, and chemotherapy, tumor recurrence is essentially universal in cancer patients, which is due, at least in part, to tumor cell heterogeneity. One of the currently prevailing models explaining intratumoral heterogeneity is the Cancer Stem Cell (CSC) hypothesis (Figure 1). According to this model, cancer stem cells (CSCs) represent a subset of a heterogeneous cancer population that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cancer cell types found in a particular cancer sample. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple non-tumorigenic cell types. Convincing evidence indicates that CSCs are inefficiently eliminated by current therapeutic treatments and suggests that CSC persistence could be responsible for disease maintenance and/or recurrence. Developing therapeutic interventions that specifically target CSCs, an appealing strategy for improving cancer treatment, requires an understanding of how CSCs escape normal regulatory mechanisms and become malignant.

Human epidermal growth factor receptor 2 (HER2)/Neu is overexpressed in 20-30% of breast cancers and associated with aggressive phenotypes and poor prognosis. Recent research has suggested that HER2 may play a critical role in generation and maintenance of CSC. Our laboratory recently found that surface markers CD49f, CD61 and ESA are aberrantly overexpressed in mouse mammary tumor virus (MMTV)-Her2 induced mammary tumor cells. The sorted CD49fhiCD61hi subpopulation display typical characteristics of CSCs such as the increased tumorsphere formation ability and enhanced tumorigenicity both in vitro and in vivo. Further analysis of these markers revealed anomalous expansion of the luminal progenitor population in preneoplastic mammary glands of Her2/neu transgenic mice, indicating that aberrant luminal progenitors may be the cells-of-origin in MMTV-Her2/neu induced mammary tumorigenesis (Figure 2). With the successful isolation of CSCs from mammary tumors of Her2/neu transgenic mice, current members in our laboratory are utilizing combined molecular, biochemical, genomic and proteomic approaches to dissect HER2-signaling pathways in breast cancer. Interdisciplinary collaborations are established to leverage other expertise in nanotechnology and mathematical modeling to assist understanding the role of HER2 gene in the regulation of breast CSCs. Lastly, high-throughput screening of novel HER2/neu-targeted anti-cancer drugs are undergoing.

 

Figure 2. The cells-of-origin in MMTV-Her2/neu induced mammary tumorigenesis.  Mouse mammary glands may consist of a hierarchy of multipotent stem, bipotent, unipotent progenitor and differentiated cells which are delineated by different combinations of cell surface marker. Luminal progenitor cells, which are either a fraction of or derived from parity-induced mammary epithelial cells (PI-MEC), are more likely to be the direct target of MMTV-Her2/neu-induced tumorigenesis.

 

Publications

Kanojia D, Zhou W, Zhang J, Jie C, Lo PK, Wang Q and Chen H. 2012. Proteomic profiling of cancer stem cells derived from primary tumors of HER2/Neu transgenic mice. Proteomics. (in press).

Lo, PK and Chen H. 2012. Cancer stem cells and cells-of-origin in MMTV-Her2/neu induced mammary tumorigenesis. Oncogene. (in press). .

Duan X, Li H, Chen H and Q Wang. 2012. Discrimination of colon cancer stem cells using noncanonical amino acid. Chem. Commun.. 48, 9035–9037.

Sharmistha S, P.K. Lo, X Duan, Chen H*, and Wang*. 2012. Extracellular-matrix proteins regulate fate of tumor initiating cells in breast cancer. Integrative Biol.4, 897-904. (*corresponding author and top ten most accessed articles in June 2012). .

Wang S, D. Kanojia, P.K. Lo, V. Chandrashekaran, X. Duan, F.G. Berger, Q. Wang and H. Chen. 2012. Tumorspheres derived from colorectal cancer cell lines are enriched in cancer stem cells that can be preferentially eliminated by a DNA methylation inhibitor. Human Genetics and Embryology . S02-006.

Saha, S, X. Duan, L. Wu, P.K. Lo, H. Chen*, and Q. Wang*. 2012. Electrospun Fibrous Scaffolds Promote Breast Cancer Cell Alignment and Epithelial-Mesenchymal Transition. Langmuir. 28(4):2028-34. (*corresponding author). .

Lo, P. K., D. Kanojia, X. Liu, U. P. Singh, F. G. Berger, Q. Wang and H. Chen. 2012. CD49f and CD61 identify Her2/neu-Induced mammary tumor Initiating cells that are potentially derived from luminal progenitors and maintained by the integrin-TGFβ signaling. Oncogene. 31(21):2614-26. .

Kanojia D and Chen H. 2011. The microenvironment and breast cancer stem cells. Breast Cancer Cells / Book 4, ISBN 978-953-307-1332-4. Intech Publisher. p237-246.

Jo H, Lo PK, Li Y, Loison F, Green S, Wang J, Silberstein LE, Ye K, Chen H*, and Luo H*. 2011. Deactivation of Akt by a small molecule inhibitor targeting pleckstrin homology domain and facilitating Akt ubiquitination. Proc Natl Acad Sci USA. 108:6486-91. (highlighted in Nature Chem. Biol. 2011, 7:340). (*corresponding author)

Yu F, Li J, Fu, J, Chen H, Ray S, Huang S and Ai W. 2011. Kruppel-like factor 4 (KLF4) is required for self-renewal of cancer stem cells and promotes migration and invasion of mammary cancer cells. Oncogene. 30:2161-72.

Gu Y, Fu J, Lo P, Wang Q and Chen H. 2011. The effect of B27 supplement on promoting in vitro propagation of Her2/neu-transformed mammary tumorspheres. J. Biotech Res. 3:7-18.

Zhang X, Wan G, Mlotshwa S, Vance V, Berger FG, Chen H and Lu X. 2010. Oncogenic Wip1 Phosphatase is Inhibited by miR-16 in the DNA Damage Signaling Pathway. Cancer Res. 70:7176-86.

Chen H*, Pimienta G, Gu Y, Kim M-S, Chaerkady R, Gucek M, Cole RN, Sukumar S and Pandey A*. 2010. Proteomic phenotype of HER2-expressing mammary epithelial cells using SILAC. Proteomics. 10:3800-10.

Chen H, Lee JS, Liang X, Zhang H, Zhu T, Zhang Z, Taylor ME, Zahnow C, Feigenbaum L, Rein A and Sukumar S. 2008. Hoxb7 inhibits transgenic HER2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 68:3637-44.

 


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