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Binhua P. Zhou, M.D., Ph.D.

Assistant Professor
Pharmacology & Toxicology

Metastasis, the spread of cells from a primary tumor to distant sites, is the main cause of death in patients with cancer. Our long-term goal is to eliminate the incidence of cancer metastasis by understanding the molecular mechanism underlying the initial step of metastasis. The metastatic process remains incompletely characterized at the molecular and biochemical levels because metastasis is a “hidden” event that takes place inside the body and is difficult to examine. This process is believed to consist of four distinct steps that require the coordinated actions of multiple genes: invasion, intravasation, extravasation, and metastatic colonization. Using in vivo video microscopy, the initial step, the acquisition of invasive ability and motility and extracellular matrix proteolysis, culminating in the shedding of cells into the circulation either directly or via the lymphatics, is the rate-limiting step in the metastatic cascade. Beyond this step, survival of cells in the circulation, their arrest in a distant organ, and their initial extravasation are relatively efficient processes. Epithelial-mesenchymal transition (EMT), a process vital for morphogenesis during embryonic development, is attracting increasing attention from oncologists as a potential mechanism for the initial step of metastasis. Many genes implicated in EMT during embryogenesis are being discovered, one after another, to control metastasis. We are currently focusing on characterization of the functional role and regulation of Snail/Slug transcription factors in the control of EMT. Snail is a zinc-finger transcriptional repressor that was identified in Drosophila as a suppressor of the transcription of shotgun (an E-cadherin homologue) in the control of embryogenesis. Flies and mice without Snail are lethal because of severe defects at the gastrula stage during development. Expression of Snail correlates with the tumor grade and nodal metastasis of many types of tumor and predicts a poor outcome in patients with metastatic cancer. We recently found that Snail is highly unstable with a short half-life of only about 25 minutes and the activity of Snail is mainly regulated by the stability of the protein and its cellular location. We are employing biochemical, molecular, and cellular approaches to study the functional regulation of Snail in breast cancer and will apply the knowledge that we gained for the prevention, diagnosis, and treatment of metastatic breast cancer in a long run. The goal of our research program is to uncover altered signaling pathways that regulate metastasis in cancer and, by discovery these pathways, to identify molecules that may serve as the therapeutic targets for metastasis prevention.

Zhou BP, Hu MC, Miller SA, Yu Z, Xia W, Lin SY, Hung MC.  HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway.  J Biol Chem 275:8027-8031, 2000.

Yang HY, Zhou BP, Hung MC, Lee MH.  Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27.  J Biol Chem 275:24735-24739, 2000.

Zhou BP, Liao Y, Xia W, Spohn B, Lee MH, Hung MC.  Cytoplasmic localization of p21Cip1/WAF1 by Akt-induced phosphorylation in HER-2/neu-overexpressing cells.  Nat Cell Biol 3:245-252, 2001.

    News and Views: W.S. El-Deiry.  Akt takes centre stage in cell-cycle deregulation
Nature Cell Biology 3:E1-E3, 2001.

Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC.  HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.  Nat Cell Biol 3:973-982, 2001.

    Highlights: C. Brooksbank.  Oncogenes: Breaking and Entering.  Nature Review Cancer 1:96, 2001.

Zou Y, Peng H, Zhou BP, Wen Y, Wang S-C, Tsai E-M, Hung M-C.  Systemic Tumor Suppression by the Proapoptotic Gene bik.  Cancer Research 62:8-12, 2002.

Zhou BP, Hung MC.  Novel targets of Akt, p21(Cipl/WAF1), and MDM2.  Semin Oncol 29:62-70, 2002.

Zhou BP, Li YM, and Hung M-C.  HER-2/neu Signaling and HER-2/neu Therapeutic Approaches in Breast Cancer, Breast Disease 15:13-24, 2002.

Deng J, Miller SA, Wang HY, Xia W, Wen Y, Zhou BP, Li Y, Lin SY, Hung MC.  beta-catenin interacts with and inhibits NF-kappa B in human colon and breast cancer.  Cancer Cell 2:323-334, 2002.

Zhou BP, Hung MC.  Dysregulation of cellular signaling by HER2/neu in breast cancer.  Semin Oncol  30:38-48, 2003.

Li YM, Wen Y, Zhou BP, Kuo HP, Ding Q, Hung MC.  Enhancement of Bik antitumor effect by Bik mutants.  Cancer Res 63:7630-7633, 2003.

Xia W, Chen JS, Zhou X, Sun PR, Lee DF, Liao Y, Zhou BP, Hung MC.  Phosphorylation/cytoplasmic localization of p21Cip1/WAF1 is associated with HER2/neu overexpression and provides a novel combination predictor for poor prognosis in breast cancer patients.  Clin Cancer Res 10:3815-3824, 2004.

Li YM, Pan Y, Wei Y, Cheng X, Zhou BP, Tan M, Zhou X, Xia W, Hortobagyi GN, Yu D, Hung MC.  Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis.  Cancer Cell 6:459-469, 2004.

    Preview: J. L. Benovic and A. Marchese.  A new key in breast cancer metastasis.
    Cancer Cell 6:429-430, 2004.

    News and Views: S. A. Eccles and L. Paon.  Breast cancer metastasis:  when, where, how?
    Lancet 365:1006-1007, 2005.

Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC.  Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition.  Nat Cell Biol 6:931-940, 2004.

    News and Views: K. Schlessinger and A. Hall.  GSK-3b sets Snail’s pace, Nature Cell
    Biology 6:913-915, 2004.

    News: A. BreindlA Snail’s life in the fast lane: looking upstream for new cancer metastasis
    insights.  BioWorld Today 15:1-7, 2004.

Li YM, Zhou BP, Deng J, Pan Y, Hay N, Hung MC.  A hypoxia-independent hypoxia-inducible factor-1 activation pathway induced by phosphatidylinositol-3 kinase/Akt in HER2 overexpressing cells.  Cancer Res 65:3257-3263, 2005.

Zhou BP, Hung MC.  Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis.  Cell Cycle 4:772-776, 2005.

Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, Ping B, Otte AP, Hung MC. Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310:306-10, 2005.

Postdoctoral Position

A postdoctoral position is immediately available to study the epithelial-mesenchymal transition (EMT) and cancer metastasis at the Sealy Center for Cancer Cell Biology. Outstanding individuals who are interested in the problems of cancer metastasis and are eager to reveal the molecular mechanisms that govern this process are encouraged to apply. Interested candidates are invited to forward their CV and names (emails) of three references to:

Binhua P. Zhou, MD., Ph.D.
Assistant Professor
The Sealy Center for Cancer Cell Biology
The University of Texas Medical Branch
Galveston, TX, 77555-1048
e-mail: bpzhou@utmb.edu

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  Last Revised:  January 18, 2008