Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 27; pp. 11121 - 11126
• Main Authors: Lee, Shuet Theng, Feng, Min, Wei, Yong, Li, Zhimei, Qiao, Yuanyuan, Guan, Peiyong, Jiang, Xia, Wong, Chew Hooi, Huynh, Kelly, Wang, Jinhua, Li, Juntao, Karuturi, K. Murthy, Tan, Ern Yu, Hoon, Dave S. B., Kang, Yibin, Yu, Qiang
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.07.2013; National Acad Sciences
• Subjects: Animals; Biological Sciences; Breast cancer; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell growth; Cell Line, Tumor; Cell lines; Clinical outcomes; Female; Gene Knockdown Techniques; Genotype & phenotype; Humans; Lungs; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; Neoplasm Invasiveness - genetics; Neoplasm Invasiveness - pathology; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Phosphatases; Phosphorylation; Protein Tyrosine Phosphatases - antagonists & inhibitors; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - metabolism; Proteins; T tests; Transplantation, Heterologous; Tumors; Up regulation; Up-Regulation - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1300873110

Efforts to improve the clinical outcome of highly aggressive triple-negative breast cancer (TNBC) have been hindered by the lack of effective targeted therapies. Thus, it is important to identify the specific gene targets/pathways driving the invasive phenotype to develop more effective therapeutics. Here we show that ubiquitin-associated and SH3 domain-containing B (UBASH3B), a protein tyrosine phosphatase, is overexpressed in TNBC, where it supports malignant growth, invasion, and metastasis largely through modulating epidermal growth factor receptor (EGFR). We also show that UBASH3B is a functional target of anti-invasive microRNA 200a (miR200a) that is down-regulated in TNBC. Importantly, the oncogenic potential of UBASH3B is dependent on its tyrosine phosphatase activity, which targets CBL ubiquitin ligase for dephosphorylation and inactivation, leading to EGFR up-regulation. Thus, UBASH3B may function as a crucial node in bridging multiple invasion-promoting pathways, thereby providing a potential therapeutic target for TNBC.