Abstract 2465: Matrix metalloproteinase 9 promotes breast cancer through regulation of insulin-like growth factor-binding proteins

Abstract

Abstract The matrix metalloproteinase (MMP) family is a large family of extracellularly acting proteases. MMP9 is expressed by tumor infiltrating myeloid cells and promotes tumor progression in animal models of cancer. Yet, the identities of the in vivo MMP9 substrates are not well established. Furthermore, clinical trials with broad-spectrum MMP inhibitors have shown no therapeutic benefit. We compared the effects of deleting Mmp9 between the luminal mouse mammary tumor virus (MMTV)-Neu model of breast cancer, driven by expression of rodent HER2/ErbB2, and the basal-like C3(1) SV40 large T antigen (Tag) model, driven through inactivation of p53 and Rb by Tag. Interestingly, absence of MMP9 delayed tumor-onset in C3(1)-Tag mice, but had no effect in the MMTV-Neu mice. In line with these data, we found that low MMP9 expression indeed predicts good prognosis for breast cancer patients with mutant p53, but does not influence prognosis for patients with wild type p53. The insulin-like growth factor-binding protein-1 (IGFBP-1) is an established in vitro MMP9 substrate. IGFBP-1 sequesters IGF in the extracellular matrix, leading to reduced IGF receptor activity and thereby cancer cell proliferation. Proteolysis of IGFBP by MMP9 releases IGF from the matrix. Interestingly, the protein levels of IGFBP-1 were significantly increased in the C3(1)-Tag;Mmp9−/− compared to C3(1)-Tag;Mmp9+/+ tumors. In contrast, IGFBP-1 protein levels were low in the MMTV-Neu model regardless of MMP9 status. Human breast tumors did not express IGFBP-1 but instead the other family members, IGFBP-2, -3, and -4, which all are substrates for MMP9 in vitro. We found that low levels of MMP9 were a good prognostic factor only for patients with high mRNA expression levels of the IGFBPs, and not for patients with low levels of the IGFBPs. Our findings from mouse models and human patients suggest that MMP9 promotes tumor progression in breast cancer via proteolysis of IGFBPs. Furthermore, a lack of stratification of patients based on both MMP9 and IGFBPs levels might explain why MMP inhibitors showed no clinical benefit against breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2465. doi:1538-7445.AM2012-2465