University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
Zena Werb, PhD

Zena Werb, PhD

Professor and Vice-Chair, Department of Anatomy, UCSF; Associate Director for Basic Science, UCSF Helen Diller Family Comprehensive Cancer Center

Cancer Center Program Memberships

Cancer Immunology

Research Summary

I have led projects on breast cancer and the environment, concentrating on puberty as the window of susceptibility for the past 12 years. My expertise in breast development, breast cancer, and the epithelial microenvironment has been developed over three decades. I have concentrated on the molecular mechanisms involved in extracellular matrix remodeling and inflammatory cell function in mammary development and breast cancer. We have developed and used a variety of new technologies and models ranging from molecular biology to genetically engineered mouse models to intravital microscopy and 3D culture models. We have published over 450 scientific papers.

My major interest is in driving the field of the extracellular microenvironment in development, inflammation, fibrosis, and tumor biology forward technically and conceptually. Another goal is to determine insights from mammary development that help explain breast stem cells, and susceptibility to cancer development and metastasis. My research program has been characterized by innovation and thoroughness. I have considerable experience in administering projects with collaborations and co-authored publications. I have also put considerable effort into mentoring young scientists and have trained more than 70 students and postdoctoral fellows.

Education

University of Toronto, Toronto, Canada, B.Sc., 1966, Biochemistry
Rockefeller University, New York, NY, Ph.D., 1971, Cell Biology
Strangeways Research. Laboratory, Cambridge, U.K., Postdoc., 1971-73, Protein Chemistry


Professional Experience

  • 1973-1975
    Research Scientist, Strangeways Res. Lab., Cambridge, U.K.
  • 1975-1976
    Visiting Assistant Professor of Medicine, Dartmouth Medical School, Hanover, NH
  • 1976-1980
    Asst. Professor of Radiobiology, Radiology, Univ. of California, San Francisco
  • 1979-1980
    Asst. Professor of Anatomy, UCSF
  • 1980-1983
    Assoc. Professor of Anatomy and Radiology, UCSF
  • 1983-present
    Professor of Anatomy, UCSF
  • 1985-1986
    Visiting Prof. (Lab. of N.J. Proudfoot), Sir William Dunn School of Pathology, Univ. of Oxford, U.K.
  • 1998
    Visiting Professor, Institut Curie Paris
  • 1999-present
    Vice-chair, Dept of Anatomy, UCSF
  • 2006-2007
    Visiting Professor, Max-Planck Institute for Biochemistry, Martinsried, Germany

Honors & Awards

  • 1971-1973
    Fellow, Medical Research Council of Canada
  • 1982
    R.R. Bensley Memorial Lecturer of the American Association of Anatomists
  • 1985-1986
    Fellow, John Simon Guggenheim Foundation
  • 1986
    Muriel Trotter Lecturer, Washington University, St. Louis
  • 1993-1994
    Sigma Xi National Lecturer
  • 1996
    FASEB Excellence in Science Award
  • 1997
    Chitra Biswas Memorial Lecturer, Tufts Medical School
  • 1998
    Rothschild/Mayent Fellowship, Institut Curie, Paris
  • 1998
    Earl Benditt Distinguished Lecturer, University of Washington
  • 1999
    J.L. Melnick Lecturer, Baylor College of Medicine
  • 1999
    Biosciences Distinguished Lecturer, Lawrence Berkeley National Laboratory
  • 2000
    Gwendolyn J. Stewart Award, Temple University
  • 2001
    Charlotte Friend Lecturer, AACR
  • 2001
    44th Faculty Research Lecturer, UCSF
  • 2001
    H.B. Parker Lecture, Pacific Northwest National Laboratory
  • 2002
    Elected Member, Institute of Medicine
  • 2003
    Elected Fellow, American Academy of Arts and Sciences
  • 2003
    Doctor of Medicine (honoris causa), University of Copenhagen
  • 2004
    Schlessinger Lecture, Beth Israel Deaconess Medical Center, Harvard Medical School
  • 2004
    A. S. Wiener Lecture, New York Blood Center
  • 2005
    Maud L. Menten Lecturer, University of Pittsburgh
  • 2006
    Alexander von Humboldt Research Award
  • 2007
    E.B. Wilson Medal, American Society for Cell Biology
  • 2009
    Colin Thomson Memorial Medal, Association for International Cancer Research
  • 2010
    Elected Member, National Academy of Sciences
  • 2010
    American Society for Cell Biology, Women in Cell Biology Senior Award
  • 2011
    Zero Breast Cancer 2011 Community Breast Cancer Research Award
  • 2018
    AACR Distinguished Lectureship in Breast Cancer Research
  • 2019
    2019 Fellow of the AACR Academy

Selected Publications

  • Werb, Z., P.M. Tremble, O. Behrendtsen, E. Crowley & C.H. Damsky (1989). Signal transduction through the fibronectin receptor induces metalloproteinase gene expression. J. Cell Biol. 109: 877-889. PMID: 2547805
  • Sympson, C.J., R.S. Talhouk, et al. (1994). Targeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement membrane for tissue-specific gene expression. J. Cell Biol. 125: 681-693. PMID: 8175886
  • Vu, T. H., J. M. Shipley, et al. (1998). MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell. 93:411-422. PMID: 9590175
  • Sternlicht, M. D., A. Lochter, et al. (1999). The stromal proteinase MMP-3/stromelysin-1 promotes mammary carcinogenesis. Cell. 98: 137-146. PMID: 10428026
  • Bergers, G., R. Brekken, et al. (2000). Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2: 737-744. PMID: 11025665
  • Coussens, L. M., C. L. Tinkle, D. Hanahan & Z. Werb (2000). MMP-9 supplied by bone marrow-derived cells regulates skin carcinogenesis. Cell. 103: 481-490. PMID: 11081634
  • Coussens, L. M. & Z. Werb (2002). Inflammation and cancer. Nature 420:860-867. PMID: 12490959
  • Egeblad, M. & Z. Werb (2002). New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2: 163-176. PMID: 11990853
  • Heissig, B., K. Hattori, et al. (2002). Mobilization of stem cells from the bone marrow niche requires MMP-9-mediated release of Kit ligand. Cell. 109: 625-637. PMID: 12062105
  • Weaver, V. M., S. Lelievre, et al. (2002). beta4 Integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell. 2: 205-216. PMID: 12242153
  • Wiseman, B. & Z. Werb (2002). Stromal effects on mammary gland development and breast cancer. Science. 296:1046-1049. PMID: 12004111
  • Yan, Y., K. Shirakabe & Z. Werb (2002). The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G-protein coupled receptors.J. Cell Biol. 158:221-226.PMID: 12119356
  • Colnot, C., Z. Thompson, T. Miclau, Z. Werb & J. A. Helms (2003). Altered bone regeneration in the absence of MMP9. Development. 130: 4123-4133. PMID: 12874132
  • Hamano, H., M. Zeisberg, et al. (2003). Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell. 3:589-601. PMID: 12842087
  • Li, Y., B. Welm, et al. (2003). Evidence that transgenes encoding components of the Wnt signaling pathway preferentially induce mammary cancers from progenitor cells. Proc. Natl. Acad. Sci. USA. 100: 15853-15858. PMID: 14668450
  • Parisi, T., A. R. Beck, et al. (2003). Cyclins E1 and E2 are required for endoreplication in placental trophoblast giant cells. EMBO J. 22: 4794-4803. PMID: 12970191
  • Wiseman, B.S., M. D. Sternlicht, et al. (2003). Site-specific positive and negative activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis. J. Cell Biol. 162:1123-1133.PMID: 12975354
  • Chantrain, C. F., H. Shimada, et al. (2004). Stromal matrix metalloproteinase-9 (MMP-9) regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res. 64: 1675-1686. PMID: 14996727
  • Cases, S., P. Zhou, et al. (2004). Development of the mammary gland requires DGAT1 expression in stromal and epithelial tissues. Development. 131: 3047-3055. PMID: 15163627
  • Stickens, D., D. J. Behonick, et al. (2004). Altered endochondral bone formation in matrix metalloproteinase-13 deficient mice. Development. 131: 5883-5895. PMID: 15539485
  • Atabai K., R. Fernandez, et al. (2005). Mfge8 is critical for mammary gland remodeling during involution. Mol. Biol. Cell. 16:5528-5537. PMID: 16195353
  • Carlson, T. R., Y. Yan, et al. (2005). Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc. Nat. Acad. Sci. USA 102: 9884-9889. PMID: 15994223
  • Heissig, B., S. Rafii, et al. (2005). Low-dose irradiation promotes tissue revascularization through Kit-ligand mediated release of VEGF from mast cells and MMP-9 mediated mobilization of endothelial progenitors. J. Exp. Med. 202:739-750. PMID: 16157686
  • Littlepage, L.E., M. Egeblad & Z. Werb (2005). Coevolution of cancer and stromal cellular responses. Cancer Cell. 7:499-500. PMID: 15950897
  • Liu, Z., X. Zhou, L. A. Diaz, R. M. Senior & Z. Werb (2005). Synergy between a plasminogen cascade and MMP-9 in autoimmune disease. J. Clin. Invest. 115: 879-887. PMID: 15841177
  • Morimoto-Tomita, M., K. Uchimura, et al. (2005). Sulf-2, an extracellular heparan sulfate endosulfatase, is upregulated during breast cancer progression and is proangiogenic. Neoplasia. 7: 1001-1010. PMID: 16331886
  • Ortega, N., D. J. Behonick, C. Colnot, D. H. Cooper & Z. Werb (2005). Galectin-3 is a downstream regulator of MMP-9 function during endochondral bone formation. Mol. Biol. Cell. 16: 3028-3039. PMID: 15800063
  • Radisky, D. C., D. D. Levy, et al. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 436:123-127. PMID: 16001073
  • Song, S., A. J. Ewald, W. Stallcup, Z. Werb & G. Bergers (2005). PDGFR+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nature Cell. Biol. 7: 870-879. PMID: 16113679
  • Sternlicht, M.D., S.W. Sunnarborg, H. Kouros-Mehr, Y. Yu, D. C. Lee & Z. Werb (2005). Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin. Development. 132:3923-3933. PMID: 16079154
  • Stickens, D., B. M. Zak, N. Rougier, J. D. Esko & Z. Werb (2005). Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development. 132:5055-5068. PMID: 16236767
  • Wall, S., E. Werner, Z. Werb & Y. A. DeClerck (2005). Discoidin domain receptor 2 mediates tumor cell cycle arrest induced by fibrillar collagen. J. Biol. Chem. 280:40187-4019. PMID: 16186104
  • Greenlee, K., D. B. Corry, et al. (2006). Proteomics identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. J. Immunol. 177: 7312-7321. PMID: 17082650
  • Hsu, J.-Y. C., R. McKeon, et al. (2006). Matrix metalloproteinase-2 facilitates wound healing events that promote functional recovery after spinal cord injury. J. Neurosci. 26 :9841-9850. PMID: 17005848
  • Kouros-Mehr, H. & Z. Werb (2006). Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev. Dyn. Oct 12; [Epub ahead of print] PMID: 17039550
  • Kouros-Mehr, H., E. M. Slorach, M. D. Sternlicht & Z. Werb (2006). GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. In press.
  • Lum, D.H., J. Tan, S. D. Rosen & Z. Werb (2006). Gene trap disruption of the mouse heparan sulfate 6-O-endosulfatase, Sulf2. Mol. Cell. Biol. In press.
  • Lund, L.R., K. A. Green, et al. (2006). Plasminogen activation independent of uPA and tPA maintains skin wound healing in gene-deficient mice. EMBO J. 25:2686-2697. PMID: 16763560
  • Sternlicht, M.D., H. Kouros-Mehr, P. Lu & Z. Werb (2006). Hormonal and local control of mammary branching morphogenesis. Differentiation. 74:365-381. PMID: 16916375
  • Sternlicht, M. D., A. M. Dunning, et al. (2006). Prognostic value of PAI1 in invasive breast cancer: evidence that tumor-specific factors are more important than genetic variation in regulating PAI1 expression. Canc. Epidemiol. Biomarkers. Prev. In press.
  • Uchimura, K., M. Morimoto-Tomita, et al. (2006). HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1 and SDF-1. BMC Biochemistry. 7:2. PMID: 16417632
  • Zeisberg, M., M. Khurana, et al. (2006). Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med. 3:e100. PMID: 16509766