Abstract 1975: Role and activation mechanisms of myeloid zinc finger-1 (MZF1) in ErbB2-induced breast cancer invasion

Abstract

Abstract ErbB2 overexpression gives rise to a highly invasive, aggressive phenotype associated with an increased activity of lysosomal cysteine cathepsins B and L and with a pericellular accumulation of lysosomes at the close vicinity of the cell membrane, enabling lysosomal exocytosis and secretion of lysosomal contents to the extracellular space. We recently showed that ErbB2 expression level correlates positively with cysteine cathepsin B and L levels in primary breast cancer and that ErbB2 regulates the expression of cathepsins B and L leading to their increased activity in several ErbB2-positive breast cancer cell lines. We found that the increased cysteine cathepsin activity is essential for the invasion of ErbB2 overexpressing breast cancer cells in 3-dimensional (3D) Matrigel cultures and that it is mediated by a novel signaling network that involves TGFβR, ERK2-MAPK, PAK4, PKCα and CDC42bpβ kinases and two transcription factors, Myeloid Zinc Finger 1 (MZF1) and ETS1, which regulate the ErbB2-induced expression of cathepsins B and L. We currently work on understanding the mechanisms that increase the transcriptional activity of MZF1 in breast cancer. Thus far we have identified two basic mechanisms that can increase MZF1 target gene expression: cancer-induced, increased levels of MZF1 and ErbB2 signaling-induced, increased transcriptional activity of MZF1. Our results thus far show that the level of MZF1 can be directly downregulated by specific, non-coding RNAs. The cancer-induced increase in the MZF1 level is most likely due to changes in the expression of these non-coding RNAs. Preliminary data employing two-dimensional SDS-PAGE as well as the factual involvement of several kinases downstream of ErbB2 for its transcriptional activity, suggests that MZF1, a prominent phosphoprotein, is activated by phosphorylation in response to ErbB2 signaling. Towards this end we have set up various experiments to verify the phosphorylation of MZF1 in response to ErbB2 signaling. We now aim at the identification of the ErbB2-regulated phosphorylation sites. With this work we expect to collect more information about the molecular mechanisms underlying ErbB2-induced invasion. Increased knowledge of the mechanisms is expected to enable the development of novel therapies and biomarkers for aggressive, ErbB2-positive breast cancer. Citation Format: Tuula Kallunki, Ditte M. Brix, Knut Kristoffer B. Clemmensen, Siri A. Tvingsholm, Bo Rafn, José Moreira, Irina Gromova, Marja Jäättelä. Role and activation mechanisms of myeloid zinc finger-1 (MZF1) in ErbB2-induced breast cancer invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1975. doi:10.1158/1538-7445.AM2015-1975