The matrix metalloprotease (MMP) family of enzymes has been implicated in invasion and metastasis. In the previous granting period, the applicant was able to show that expression of MMP-9, one of the members of this family, is required for metastasis by transformed rat embryo cells. Since MMP-9 expression is found to be increased in many human carcinomas, the implication is that MMP-9 may contribute to invasion or metastasis in these cancers as well. In this application the applicant intends to explore the involvement of MMP-9 as well as MMP-2 in other metastasis model systems including a human colon carcinoma system and a murine mammary carcinoma system. This will be done both by augmenting expression and by inhibiting it. The MMPs are secreted in latent forms that must be cleaved to result in enzymatically active forms. Therefore, in order to test the role of enzyme activation, the applicant intends to engineer vectors which will lead to autoactivatable forms. The applicant will explore the sequence elements responsible for transcriptional activity of the MMP-9 promoter in tissue culture, defining the sites in the promoter that are responsible for induction both in cells that constitutively express MMP-9 and in cells that express MMP-9 after induction. In the previous granting period, the applicant demonstrated that MMP-9 expression could be induced in tumor stroma by the interaction of the stromal cells with the tumor cells. The studies herein will allow the applicant to define the transcriptional elements responsible for the regulation of induction by cell-cell contact. The applicant will generate a transgenic mouse with the MMP-9 promoter linked to a reporter gene, beta-galactosidase. By following the beta- galactosidase activity in this mouse the applicant will be able to confirm the patterns of MMP-9 expression during development and in the adult mouse. In an initiator-promoter model of skin carcinogenesis, the applicant will be able to follow the induction of MMP-9 during tumor progression. If she generates mice with mutations in the MMP-9 promoter, the applicant can also determine which elements are essential not only for transcription in cells, but also in transgenic animals during development or during tumor progression.
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