Abstract
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer commonly resistant to therapeutics that have been successful in increasing survival in patients with estrogen receptor-positive (ER(+)) and HER2(+) breast cancer. As such, identifying factors that contribute to poor patient outcomes and mediate the growth and survival of TNBC cells remain important areas of investigation. MTBP (MDM2-binding protein), a gene linked to cellular proliferation and a transcriptional target of the MYC oncogene, is overexpressed in human malignancies, yet its contribution to cancer remains unresolved. Evaluation of mRNA expression and copy number variation data from The Cancer Genome Atlas (TCGA) revealed that MTBP is commonly overexpressed in breast cancer and 19% show amplification of MTBP. Increased transcript or gene amplification of MTBP significantly correlated with reduced breast cancer patient survival. Further analysis revealed that while MTBP mRNA is overexpressed in both ER(+) and HER2(+) breast cancers, its expression is highest in TNBC. MTBP mRNA and protein levels were also significantly elevated in a panel of human TNBC cell lines. Knockdown of MTBP in TNBC cells induced apoptosis and significantly reduced TNBC cell growth and soft agar colony formation, which was rescued by expression of shRNA-resistant Mtbp. Notably, inducible knockdown of MTBP expression significantly impaired TNBC tumor growth, in vivo, including in established tumors. Thus, these data emphasize that MTBP is important for the growth and survival of TNBC and warrants further investigation as a potential novel therapeutic target. IMPLICATIONS: MTBP significantly contributes to breast cancer survival and is a potential novel therapeutic target in TNBC.