Mixed Lineage Kinase 4 (MLK4) is a serine/threonine kinase that plays a role in a variety of cellular processes, including migration, apoptosis and proliferation. It belongs to the family of MAP3 kinases, which regulate the activity of specific MAPKs (mitogen-activated protein kinases). MLK4 is the least described member of the family and it was proved to act as a functional MAP3 kinase that activates the JNK, ERK and NFκB pathways. The rationale of this project is based on the recent data showing gene amplification and mRNA upregulation of MLK4 in invasive breast carcinoma at the frequency of 23%. Here, we performed a series of experiments aiming to characterize the role of MLK4 in breast cancer development and progression. We started from identification of breast cancer cell lines that express high endogenous level of MLK4. Since clinical data indicated that MLK4 expression was higher in triple-negative breast cancer (TNBC), comparing to other breast cancer subtypes, we decided to further study the role of MLK4 in TNBC. We have generated cell lines with doxycycline-inducible knock-down of MLK4, HCC1806 and HCC1599, and we found that MLK4 depletion resulted in reduced cell proliferation. We also observed that the knock-down of MLK4 in these conditions caused the reduction in size of the spheroids. Moreover, we noticed that when MLK4 is depleted in HCC1806 cells, the migration and invasion was significantly impaired. Lastly, our results of immunohistochemistry in samples from breast cancer patients showed that higher levels of MLK4 in TNBC samples significantly correlated with the occurrence of lymph node metastasis. Currently, we are investigating molecular pathways such as JNK, MEK/ERK and NF-κB, that might be affected by knock-down of MLK4. Collectively, our findings indicate that high levels of MLK4 promote aggressive phenotype of breast cancer cells, by increasing their migratory and invasive potential.

Citation Format: Prelowska MK, Mehlich D, Lazniewski M, Kaminska K, Gorczynski AS, Korwat A, Sokolowska O, Golab J, Biernat W, Plewczynski D, Brognard J, Nowis D, Marusiak AA. The role of MLK4 amplification in progression of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-09-07.

©2019 American Association for Cancer Research.
2019
American Association for Cancer Research.