APPLICATIONS OF TECHNOLOGY:
- Anti-cancer drug development
- Cancer diagnostics
- Breast cancer research
- Describes mechanism for mammary cell branching
- Identifies functions of non-catalytic MMP domains in normal tissue patterning
- Identifies potential role of non-catalytic domains in tumorigenic invasion
- Presents new MMP inhibitor targets for cancer therapeutics
Berkeley Lab researchers led by Mina J. Bissell and Hidetoshi Mori have identified that non-catalytic sections of the matrix metalloproteinase proteins (MMPs), such as MMP3 and MMP14, are a target for new drugs that might block cancerous breast tissue growth or metastasis.
The researchers discovered that MMPs promote the branching of normal mammary epithelial cells during puberty. In addition, the non-catalytic domain is responsible for the cellular sorting required for the formation of mammary tubules, and this role is subverted during breast cancer progression. This suggests that the non-catalytic domains of MMPs, such as the transmembrane/cytoplasmic domain of MMP14, rather that the MMP catalytic domain, might be the correct target for drugs that would block tumor growth or metastases. Similarly, biomarkers that isolate unusual or excessive non-catalytic domain activity could serve a purpose in diagnosing and tracking tumor progression.
In the past, the primary function of MMPs was assumed to be the capacity of the catalytic domain to break down proteins and create a path for cells to invade through the extracellular matrix. However, past efforts to develop therapeutics blocking MMPs’ catalytic domain have failed because the drugs caused severe side effects.
The discovery of an important role for non-catalytic domains of MMPs in regulating cellular invasion and branching has far reaching implications. Although the role of faulty MMP regulation is well established in breast cancer, these proteases have also been shown to be a causative factor in cancers of the lung, colon, skin, prostate, ovary, pancreas, tongue, mouth, and stomach. Further exploration of pathways and cellular signaling that involve the non-catalytic domains of this crucial family of proteins could prove valuable in the effort to understand disease processes and develop new cancer drugs.
DEVELOPMENT STAGE: Proven principle.
STATUS: Patent pending. Available for licensing or collaborative research.
FOR MORE INFORMATION:
Correia, A.L., Mori, H., Chen, E.I., Schmitt, F.C., Bissell, M.J., “The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90β,” Genes Dev. 2013 27(7):805-817.
Mori, H., Lo, A.T., Inman, J.L., Alcaraz, J., Ghajar, C.M., Mott, J.D., Nelson, C.M., Chen, C.S., Zhang, H., Bascom, J.L., Seiki, M., Bissell, M.J. “Transmembrane/cytoplasmic, rather than catalytic, domains of Mmp14 signal to MAPK activation and mammary branching morphogenesis via binding to integrin β1,” Development, Vol. 140, pp. 343-352 (2013).
Mori, H., Gjorevski, N., Inman, J.L., Bissell, M.J., Nelson, C.M., "Self-organization of engineered epithelial tubules by differential cellular motility," PNAS, Vol. 106, No. 35 pp. 14890-4895 (2009).
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REFERENCE NUMBER: IB-2445