A transcriptional regulatory mechanism in invasive breast cancer; role of AIB-1 and PEA-3.

Abstract

Abstract Abstract #2056 The invasive potential of cancer cells is mediated in part through the action of matrix metalloproteinases (MMP), which degrade the extra-cellular membrane and promote metastasis. The transcription regulatory region of MMP genes contains binding sites for Ets transcription factors. While the underlying mechanism of MMP regulation is unclear, the Ets transcription factor PEA3 has been shown to be involved. We have previously reported that expression of PEA-3 is associated with the co-activator AIB-1, HER2 positivity, metastasis, and reduced disease free survival. Furthermore, an AIB-1 knockout mouse exhibited PEA-3 dependant MMP production, resulting in reduced metastatic potential. In this study we combined translational and molecular approaches to study the role of PEA-3 and AIB-1 in the transcriptional regulation of MMPs in breast cancer.
 The expression of PEA-3, AIB-1, and MMP-9 was assessed in a tissue microarray of breast cancer patients (n=560). Strong associations were observed between both PEA-3, AIB-1, and their target gene MMP-9 (p= 0.007, p= 0.0016 respectively). In HER2 positive patients PEA-3, but not AIB-1 or MMP-9, was associated with reduced disease free survival (p<0.0044, p= 0.4491, and p= 0.0666 respectively). A stable breast cancer cell line over-expressing PEA-3 was created. Upregulation of the growth factor pathway in this cell line resulted in the increased expression of MMP-9. Furthermore, silencing AIB-1 resulted in reduced MMP-9 production in breast cancer cells in vitro.
 Ets transcription factors are important mediators of breast tumour invasion. This data supports a role for the transcription factor PEA-3 and its co-activator AIB-1 in the production of MMPs in breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2056.