Binhua P. Zhou, M.D., Ph.D.
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,
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. Breindl. A 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.
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.
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
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.,
The Sealy Center for Cancer Cell Biology
The University of Texas Medical Branch
Galveston, TX, 77555-1048
Home | Mission | Investigators
| Transgenic Mouse
Facility | PCR Core
Facility | Human Tumor
Bank | Career Opps
Cancer Cell Biology Track |
Fellowship | Seminars | News
| Related Links |
This site published by
the Sealy Center for Cancer Cell Biology.
Copyright © 2000-2005
The University of Texas Medical Branch. Please
and Internet guidelines.
Revised: January 18, 2008