GABARAP Suppresses EMT and Breast Cancer Progression Via the AKT/mTOR Signaling Pathway
Background: Recent studies document that γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) plays an important role in cancer autophagy. However, little is known about its role in tumor invasion, migration and metastasis. Here, the authors investigated the expression and significance of GABARAP in breast cancer. Method: A large group of clinical samples was assessed to detect GABARAP expression and its associations with clinicopathological features and prognosis. Gain- and
... rognosis. Gain- and loss-of-function experiments in cell lines and mouse xenograft models were performed to elucidate the function and underlying mechanisms of GABARAP-regulated tumor progression. Results: We analyzed GABARAP levels in clinical breast cancer samples and cell lines and confirmed that GABARAP was negatively correlated with advanced clinicopathologic features, such as tumor size (P=0.025) and TNM stage (P=0.001). Importantly, patients with low GABARAP levels had a poor prognosis (p = 0.0047). Functionally, our data revealed that GABARAP can inhibit proliferation, migration and invasion in vitro and in vivo. Importantly, low levels of GABARAP induced epithelial-mesenchymal transition (EMT), one of the most important mechanisms for the promotion of tumor metastasis, in breast cancer cells. Mechanistically, low levels of GABARAP increased the levels of p-AKT (S473) and p-mTOR (S2448), and a specific AKT pathway inhibitor reversed the downregulation of GABARAP-induced tumor progression. In clinical breast cancer specimens, immunohistochemistry (IHC) revealed that the distribution and intensity of GABARAP expression were negatively correlated with those of matrix metalloproteinase (MMP) 2 (P=0.0013) and MMP14 (P=0.019). Conclusions: Collectively, these data indicated that GABARAP suppressed the malignant behaviors of breast cancer cells, illuminating that the possible mechanism acts via the AkT/mTOR pathway. Targeting GABARAP may provide a potential diagnosis and treatment strategy for breast cancer.