Altered Microenvironment Promotes Progression of Pre-Invasive Breast Cancer: myoepithelial expression of αvβ6 integrin in DCIS identifies high-risk patients and predicts recurrence
Menée sur 532 échantillons prélevés sur des patientes atteintes d'un carcinome canalaire in situ, puis in vitro et in vivo, cette étude suggère que la mesure de l'expression d'une intégrine (αvβ6) dans les cellules myoépithéliales permet de prédire la progression et la récidive de la maladie
Purpose: This study investigated the functional and clinical significance of integrin αvβ6 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 αvβ6 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 αvβ6 expression, were used to measure the effect of αvβ6 on growth and invasion of tumor cell lines in vitro, and in a xenograft mouse model. Involvement of TGFβ 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 αvβ6 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 αvβ6 drives myoepithelial cells to promote tumor cell invasion in vitro and enhances mammary tumor growth in vivo. The tumor promoting effect of αvβ6-positive myoepithelial cells is dependent on TGFβ-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 αvβ6 on myoepithelial cells generates a tumor-promoter function through TGFβ up-regulation of MMP-9. These data suggest expression of αvβ6 may be used to stratify patients with DCIS.
Clinical Cancer Research , résumé, 2013