Aurora B induces epithelial–mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis

• Published in: Oncogene Vol. 39; no. 12; pp. 2550 - 2567
• Main Authors: Zhang, Jianchao, Lin, Xinxin, Wu, Liufeng, Huang, Jia-Jia, Jiang, Wen-Qi, Kipps, Thomas J., Zhang, Suping
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2020; Nature Publishing Group
• Subjects: 13; 13/1; 13/105; 13/109; 13/44; 13/51; 13/89; 13/95; 14/34; 38/22; 59; 59/5; 631/67/395; 64; 692/53/2423; 82; AKT protein; Animals; Apoptosis; Aurora B protein; Aurora Kinase B - antagonists & inhibitors; Aurora Kinase B - metabolism; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinoma, Ductal - metabolism; Carcinoma, Ductal - pathology; Care and treatment; Cell Biology; Cell Line, Tumor; Cell proliferation; Complications and side effects; Down-Regulation; Enzyme inhibitors; Epithelial-Mesenchymal Transition; Female; Gene expression; Genetic aspects; Glycogen Synthase Kinase 3 beta - metabolism; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Lung Neoplasms - secondary; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Mice, Inbred NOD; Neoplasm Invasiveness; Neoplasm Metastasis; Oct-4 protein; Octamer Transcription Factor-3 - metabolism; Oncology; Organophosphates - pharmacology; Phosphorylation; Phosphotransferases; Protein Kinase Inhibitors - pharmacology; Protein Stability; Protein-serine/threonine kinase; Quinazolines - pharmacology; Risk factors; Signal Transduction; Snail Family Transcription Factors - metabolism; Triple Negative Breast Neoplasms - metabolism; China
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1165-z

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial–mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.