Altered Microenvironment Promotes Progression of Preinvasive Breast Cancer: Myoepithelial Expression of αvβ6 Integrin in DCIS Identifies High-risk Patients and Predicts Recurrence

Purpose: This study investigated the functional and clinical significance of integrin alpha v beta 6 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 alpha v beta 6 by immunohistochemistry and ability to predict recurrence and progression assessed in an independent, uniquecohort of DCIS cases with long-term follow-up. Primary myoepithelial cells and myoepithelial cell lines, with and without alpha v beta 6 expression, were used to measure the effect of alpha v beta 6 on growth and invasion of tumor cell lines in vitro and in a xenograft mouse model. Involvement of TGF beta 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 alpha v beta 6 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 avb6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor-promoting effect of alpha v beta 6-positive myoepithelial cells is dependent on TGF beta-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 alpha v beta 6 on myoepithelial cells generates a tumor promoter function through TGFb upregulation of MMP-9. These data suggest that expression of alpha v beta 6 may be used to stratify patients with DCIS. (C) 2013 AACR.