PURPOSE: This study investigated the functional and clinical significance of integrin alphavbeta6 upregulation in myoepithelial cells of ductal carcinoma in situ (DCIS). EXPERIMENTAL DESIGN: Archival samples of DCIS and DCIS with associated invasion (n = 532) were analyzed for expression of alphavbeta6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, unique cohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without alphavbeta6 expression, were used to measure the effect of alphavbeta6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGFbeta signaling was established using mink lung epithelial cell (MLEC) assay and antibody inhibition, and expression and activation of matrix metalloproteinase (MMP)-9 established by Real Time-PCR and zymography. RESULTS: Expression of alphavbeta6 is significantly associated with progression to invasive cancer (P < 0.006) and with recurrence over a median follow-up of 114 months in a series of matched DCIS cases treated with local excision. We show that expression of alphavbeta6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of alphavbeta6-positive myoepithelial cells is dependent on TGFbeta-driven upregulation of MMP9 and can be abrogated by inhibiting this pathway. CONCLUSION: These findings indicate that altered myoepithelial cells in DCIS predict disease progression and recurrence and show that upregulation of alphavbeta6 on myoepithelial cells generates a tumor promoter function through TGFbeta upregulation of MMP-9. These data suggest that expression of alphavbeta6 may be used to stratify patients with DCIS.