Ernest Orlando Lawrence Berkeley National Laboratory

APPLICATIONS OF TECHNOLOGY:

• Breast cancer research
• In vivo testing of potential drug therapies for breast cancer and leukemia

ADVANTAGES:

• Novel in vivo model to study initiation and promotion of breast cancer and leukemia

ABSTRACT: The extracellular matrix (ECM) is an important regulator of mammary epithelial cell function and morphology during normal development and appears to play an important role in the progression of breast cancer. ECM-degrading metalloproteinases (MMPs) have been implicated in remodeling the ECM and tissue morphogenesis. To facilitate study of the role of MMPs in ECM remodeling and their importance in mammary gland morphogenesis, Berkeley National Laboratory scientists, Mina Bissell, Zena Werb and colleagues have generated transgenic mice that overexpress autoactivated forms of rat stromelysin in the mammary gland, under the control of the mammary gland-specific whey acidic protein (WAP) promoter. These transgenic mice express autoactivated isoforms of the matrix metalloproteinase stromelysin-L gene, which disrupts the balance between proteinases and inhibitors and affects basement membrane integrity in the mammary gland. Increased tumor incidence in these mice permits research into the suggestion that disruption of the basement membrane can lead to breast cancer. Many of these transgenic mice also develop leukemia, which makes them useful as a model for that disease as well.

STATUS: Available for licensing/bailment

REFERENCE NUMBER: IB-1113

PUBLICATIONS:

"Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix." Boudreau N, Sympson C.J, Werb Z and Bissell M.J. Science 267:891-893 (1995).

"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" [published erratum appears in J Cell Biol 1996 Feb;132(4):following 752] C.J. Sympson, R.S. Talhouk, C.M. Alexander, J.R. Chin, S.M. Clift, M.J. Bissell, and Z. Werb, J. Cell Biol. 1994 125: 681-693

"Overexpression of Stromelysin-1 in the Mouse Mammary Gland Leads to Epithelial Hyperplasia and Tumor Formation." C.J. Sympson, N. Thomasset, C.M. Alexander, M.J. Bissell, and Z. Werb. Journal of Cell Biology 1994.

"Overexpression of Stromelysin-1 Modifies Mammary Gland Stroma in Transgenic Mice." N. Thomasset, C.J. Sympson, L. Lund, Z. Werb, M.J. Bissell. Molecular Biology of the Cell 1994.

"Expression of WAP-Stromelysin Transgene in CD-1 Mice Alters Mammary Specific Gene Expression and Morphology." C.J. Simpson, R.S. Talhouk, C.M. Alexander, J.R. Chin, Z Werb, and M.J. Bissell. Molecular Biology of the Cell. 1992.

"A Critical balance between ECM-degrading proteinases and their inhibitors regulates tissue specific function." R.S. Talkhouk, C.M. Alexander, S.M. Clift, C.J Sympson, M.J. Bissell and Z. Werb. Journal of Cell Biology 1991.