Theranostics 2019; 9(1):34-47. doi:10.7150/thno.29407
Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca2+-NFAT1 Axis
1. Department of Pathology and Pathophysiology, and Department of Surgical Oncology (breast center) of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
2. Affiliated Hospital of Shaanxi University of Chinese Medicine, Xi'an712000, China
3. Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China.
*These authors contributed equally to this study.
Chen X, Cao Q, Liao R, Wu X, Xun S, Huang J, Dong C. Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca2+-NFAT1 Axis. Theranostics 2019; 9(1):34-47. doi:10.7150/thno.29407. Available from http://www.thno.org/v09p0034.htm
Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying aggressiveness in BLBC remain poorly understood.
Methods: The effects of gamma-aminobutyrate aminotransferase (ABAT) on GABA receptors, Ca2+-NFAT1 axis, and cancer cell behavior were assessed by Ca2+ imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between ABAT and Snail by luciferase reporter and ChIP assays. The effect of ABAT expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model.
Results: We showed that, compared to other subtypes, ABAT was considerably decreased in BLBC. Mechanistically, ABAT expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca2+ concentration by activating GABA-A receptor (GABAA), which contributed to the efficient activation of NFAT1 in BLBC cells. ABAT expression resulted in inhibition of tumorigenicity, both in vitro and in vivo, and metastasis of BLBC cells. Thus, loss of ABAT contributed to BLBC aggressiveness by activating the Ca2+-NFAT1 axis. In breast cancer patients, loss of ABAT expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance.
Conclusions: Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of ABAT expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca2+-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease.
Keywords: ABAT, basal-like breast cancer (BLBC), GABA, Snail, NFAT1