Background Triosephosphate isomerase 1 (TPI1), as a key glycolytic enzyme, is upregulated in multiple cancers. However, expression profile and regulatory mechanism of TPI1 in breast cancer (BRCA) remain mysterious. Methods Western blotting and immunohistochemistry (IHC) assays were used to investigate the expression of TPI1 in BRCA specimens and cell lines. TPI1 correlation with the clinicopathological characteristics and prognosis of 362 BRCA patients was analyzed using a tissue microarray. Overexpression and knockdown function experiments in cells and mice models were performed to elucidate the function and mechanisms of TPI1-induced BRCA progression. Related molecular mechanisms were clarified using co-IP, IF, mass spectrometric analysis, and ubiquitination assay. Results We have found TPI1 is highly expressed in BRCA tissue and cell lines, acting as an independent indicator for prognosis in BRCA patients. TPI1 promotes BRCA cell glycolysis, proliferation and metastasis in vitro and in vivo. Mechanistically, TPI1 activates phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway to regulate epithelial–mesenchymal transformation (EMT) and aerobic glycolysis, which is positively mediated by cell division cycle associated 5 (CDCA5). Moreover, TPI1 interacts with sequestosome-1 (SQSTM1)/P62, and P62 decreases the protein expression of TPI1 by promoting its ubiquitination in MDA-MB-231 cells. Conclusions TPI1 promotes BRCA progression by stabilizing CDCA5, which then activates the PI3K/AKT/mTOR pathway. P62 promotes ubiquitin-dependent proteasome degradation of TPI1. Collectively, TPI1 promotes tumor development and progression, which may serve as a therapeutic target for BRCA.

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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 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 epithelialmesenchymal 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. Background Breast cancer is the most common cancer in women and is the second leading cause of cancer-This study was approved by the Ethics Committee of Harbin Medical University. Samples from 87 cases of histopathologically confirmed invasive ductal breast cancer (IDC) and 48 cases of ductal carcinoma in situ (DCIS) as well as 24 samples of normal breast tissue were included in this study. The IDC patients were female, hospitalized at the Affiliated Tumor Hospital of Harbin Medical University from March 2010 to November 2010 and followed-up until March 2015. The median followup was 58.9 months (range 16.8 to 63.3 months). Formalin-fixed paraffin-embedded (FFPE) tissues and complete clinical records of the patients were collected. None of the patients had undergone preoperative chemotherapy or radiotherapy. Cell Culture The human breast cancer cell lines MDA-MB-231, MCF7, MDA-MB-468, T47D, UACC-812, MDA-MB-453, SKBR-3, and HCC70 and nontransformed breast cell line MCF-10A were obtained from the Cancer Research Institute of Heilongjian...