Altered microenvironment promotes progression of pre-invasive breast cancer: myeopithelial expression of avb6 integrin in DCIS Identifies high-risk patients and predicts recurrence

Allen, M.D., Thomas, Gareth J., Clark, S., Dawoud, M.M., Vallath, S., Payne, S.J., Gomm, J.J., Dreger, S.A., Dickinson, D.R., Pennington, C.J., Sestak, I., Cuzick, J., Marshall, J.F., Hart, I.R. and Jones, J.L. (2013) Altered microenvironment promotes progression of pre-invasive breast cancer: myeopithelial expression of avb6 integrin in DCIS Identifies high-risk patients and predicts recurrence. Clinical Cancer Research, n/a, n/a. (doi:10.1158/1078-0432.CCR-13-1504). (PMID:24150233)

Abstract

PURPOSE: This study investigated the functional and clinical significance of integrin ?v?6 up-regulation in myoepithelial cells of ductal carcinoma in-situ (DCIS).

EXPERIMENTAL DESIGN: Archival samples of DCIS and DCIS with associated invasion (n=532) were analysed for expression of ?v?6 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 ?v?6 expression, were used to measure the effect of ?v?6 on growth and invasion of tumor cell lines in vitro, and in a xenograft mouse model. Involvement of TGF? signaling was established using MLEC assay and antibody inhibition, and expression and activation of matrix-metalloproteinase (MMP)-9 established by RT-PCR and zymography.

RESULTS: Expression of ?v?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 ?v?6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor promoting effect of ?v?6-positive myoepithelial cells is dependent on TGF?-driven up-regulation 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 demonstrate that up-regulation of ?v?6 on myoepithelial cells generates a tumor-promoter function through TGF? up-regulation of MMP-9. These data suggest expression of ?v?6 may be used to stratify patients with DCIS.

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