Abstract 2687: Krüppel-like factor 8 targets matrix metalloproteinase-14 to promote breast cancer invasion and metastasis .

Abstract

Abstract Krüppel-like factor 8 (KLF8) regulates critical gene transcription and invasion events associated with cancer, including epithelial to mesenchymal transition (EMT) and extracellular matrix degradation. Here, we report a novel KLF8-to- matrix metalloproteinase-14 (MMP14) signaling that promotes human breast cancer cell EMT, invasion and metastasis. Cell-surface protein biotinylation and streptavidin pull-down showed that overexpression of KLF8 induced cell-surface accumulation of MMP14 in MCF-10A cells in a FAK-dependent manner, which was correlated with increased MMP14 activity and the ectodomain shedding of E-cadherin. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced expression and activity of MMP14 on the cell surface. Promoter reporter assays and chromatin and oligonucleotide precipitations determined that KLF8 activated the human MMP14 gene promoter both directly and indirectly via beta-catenin. Importantly, Matrigel invasion assays showed that MMP14 was required for the KLF8-induced MCF-10A cell invasion in vitro. Experiments using nude mice demonstrated that MMP-14 overexpression downstream of KLF8 in the MDA-MB-231 cells makes a significant contribution to the invasion and angiogenesis in the local primary tumors and lung metastasis. Taken together, this work identified a novel role and mechanisms for MMP14 downstream of KLF8 in the progression of breast cancer metastasis. Citation Format: Heng Lu, Liu Hu, Lin Yu, Xianhui Wang, Chao Shen, Tianshu Li, Debarati Mukherjee, Satadru Lahiri, Melissa Wason, Jihe Zhao. Krüppel-like factor 8 targets matrix metalloproteinase-14 to promote breast cancer invasion and metastasis . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2687. doi:10.1158/1538-7445.AM2013-2687