Regulation Of The Oncogenic, Invasion-Promoting Transcription Factor Myeloid Zinc Finger-1 (Mzf1) In Breast Cancer By Micrornas

INTRODUCTION: Myeloid Zinc Finger 1 (MZF1) is a transcription factor that is normally involved in myeloid differentiation. MZF1 can also be found in epithelial cancers, where it functions as an invasion and metastasis promoting oncogene. MZF1 is a central node of the invasive signaling network activated by HER2/ErbB2 in breast cancer, where MZF1 mobilizes and activates lysosomes and increases the expression of cysteine cathepsin B to promote invasion and metastasis. Thus, maintaining the sufficient expression level of MZF1 is important for the invasive signaling of breast cancer cells. RESULTS AND EXPERIMETAL PROCHEDURES: Here we show that MZF1 is essential for the invasion of breast cancer cells in 3-dimensional cultures. We also describe a possible mechanism that regulates MZF1 levels in breast cancer. By using available micro-RNA (miRNA) binding site prediction programs (www.microrna.org/), specific microRNA mimics, corresponding miRNA inhibitors e.g. locked nucleic acids, luciferase reporter assays, immunofluorescense, quantitative PCR and 3-dimensional invasion assays we show that some breast cancer specific miRNAs can regulate MZF1 RNA and protein levels and revert the malignant and invasive cellular phenotype of breast cancer cells by altering the invasion promoting functions of lysosomes. These results are supported by the analysis of breast cancer patient data from the cancer genome atlas (http://cancergenome.nih.gov) showing that MZF1 expression correlates negatively with the expression of the identified miRNAs, when using data collected from over 600 primary breast cancer tumors. SUMMARY: This study shows that MZF1 is an oncogene whose sufficient expression levels are central for breast cancer cell invasion and whose specific miRNA-mediated downregulation can inhibit breast cancer malignancy by modifying the expression of its lysosomal target genes. CONCLUSION: Cancer-associated upregulation of MZF1 increases the breast cancer malignancy. Thus finding ways to downregulate MZF1 expression or inhibit its activity can be beneficial for breast cancer therapy. Citation Format: Tuula Kallunki, Siri A. Tvingsholm, Knut K. Bundgaard Clemmensen, Ditte M. Brix, Bo Rafn, Jose Moreira, Lisa Frankel, Anders Lund, Riku Louhimo, Sampsa Hautaniemi, Irina Gromova, Marja Jaattela. Regulation of the oncogenic, invasion-promoting transcription factor myeloid zinc finger-1 (MZF1) in breast cancer by microRNAs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1999.