Despite improvement in overall survival, many patients with breast cancers still succumb to this disease. Identification of new biomarkers and safe therapeutic targets are urgently needed to improve the overall clinical outcome of breast cancer patients. Our studies discovered a RNA binding protein, MATRIN3 (MATR3), as a novel tumor suppressor. MATR3 is expressed at a significantly reduced levels in breast tumors. MATR3 inhibited short and long-term viability as well as migration and invasion of breast cancer cells. Further, MATR3 overexpression suppressed tumor growth, while its depletion induced tumor growth in orthotopic mouse tumor models. RNA seq and RNA immunoprecipitation analyses revealed that MATR3 binds and directly regulates the expression of several microtubule-associated proteins. Mechanistic studies identified MZT2B, a mitotic spindle organizing protein as a down stream effector of MATR3. MZT2B knockdown or knockout using CRISPR-CAS9 resulted in significantly decreased short and long term viability as well as reduced migration and invasion of breast cancer cells. Notably, MZT2B overexpression rescued the inhibitory effect of MATR3 overexpression on breast cancer growth. Furthermore, MATR3 overexpression downregulated expression of key microtubule nucleation protein complex including γ-tubulin and γ-tubulin ring complex protein (TUBGCP). Our data suggest that MATR3 inhibits breast cancer growth and progression by inhibiting MZT2B and consequently microtubule nucleation in breast cancers.

Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Suryavathi Viswanadhapalli, Fuyang Li, Vijay Eedunuri, Pooja Yadav, Esha Reddy, Santosh Timilsina, Saif SR Nirzhor, Benjamin C Onyeagucha, Li-Ju Wang, Yu-Chiao Chiu, Tabrez Mohammad, Nourhan Abdelfattah, Nicholas Dybdal-Hargreaves, Yidong Chen, Ratna Vadlamudi, Manjeet Rao. Matrin3 inhibits breast cancer growth by suppressing microtubule nucleation protein MZT2B [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-14.