Water channel protein AQP1 in cytoplasm is a critical factor in breast cancer local invasion.

BACKGROUND: Metastasis of breast cancer grows from the local invasion to the distant colonization. Blocking the local invasion step would be promising for breast cancer treatment. Our present study demonstrated AQP1 was a crucial target in breast cancer local invasion. METHODS: Mass spectrometry combined with bioinformatics analysis was used to identify AQP1 associated proteins ANXA2 and Rab1b. Co-immunoprecipitation, immunofluorescence assays and cell functional experiments were carried out to define the relationship among AQP1, ANXA2 and Rab1b and their re-localization in breast cancer cells. The Cox proportional hazards regression model was performed toward the identification of relevant prognostic factors. Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. RESULTS: Here, we show that the cytoplasmic water channel protein AQP1, a crucial target in breast cancer local invasion, recruited ANXA2 from the cellular membrane to the Golgi apparatus, promoted Golgi apparatus extension, and induced breast cancer cell migration and invasion. In addition, cytoplasmic AQP1 recruited cytosolic free Rab1b to the Golgi apparatus to form a ternary complex containing AQP1, ANXA2, and Rab1b, which induced cellular secretion of the pro-metastatic proteins ICAM1 and CTSS. Cellular secretion of ICAM1 and CTSS led to the migration and invasion of breast cancer cells. Both in vivo assay and clinical analysis data confirmed above results. CONCLUSIONS: Our findings suggested a novel mechanism for AQP1-induced breast cancer local invasion. Therefore, targeting AQP1 offers promises in breast cancer treatment.

The alternative splicing of intersectin 1 regulated by PTBP1 promotes human glioma progression.

Intersectin 1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which are highly regulated by alternative splicing. Our previous results showed that the two isoforms of ITSN1 displayed opposite functions: ITSN1-S promoted glioma development, while ITSN1-L exerted an inhibitory role in glioma progression. In this study, our transcriptome analysis using a large glioma cohort indicated that the ratio of ITSN1-S/ITSN1-L was positively correlated with glioma grading and poor prognosis. We identified the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as an ITSN1 pre-mRNA interaction protein through RNA pull-down assay and RNA immunoprecipitation assay. Knockdown of PTBP1 decreased the ratio of ITSN1-S/ITSN1-L. Minigene reporter assay and mutation analyses further confirmed PTBP1 targeted polypyrimidine sequences on ITSN1 exon 30 (TTGCACTTCAGTATTTT) and promoted the inclusion of ITSN1 exon 30. Subsequently, silencing PTBP1 inhibited glioma cell proliferation, migration, and invasion by down-regulating the ratio of ITSN1-S/ITSN1-L. Taken together, our study provides a novel mechanism that PTBP1 modulates the alternative splicing of ITSN1 and promotes glioma proliferation and motility by up-regulating the ratio of ITSN1-S/ITSN1-L, thereby highlighting that PTBP1 may be an attractive therapeutic target for gliomas.

Knockdown of Girdin Induced Apoptosis of Glioblastoma Cells via the Mitochondrion Signaling Pathway.

Glioblastoma is the most common primary brain tumor with poor survival rate and without effective treatment strategy. However, the influence of Girdin on human glioblastoma and the underlying molecular mechanisms have yet to be uncovered. We mainly investigated the role of Girdin in glioblastoma cells apoptosis. First, we examined Girdin expression in 90 glioma patients by using immunohistochemistry (IHC) and analyzed its association with patients' prognosis. The results showed that the expression of Girdin was positively associated with the histological grade of glioma, and glioma patients with high Girdin expression had a poor prognosis. Next, proliferation assay, Colony formation assay and Cell Counting Kit-8 (CCK-8) results showed that knockdown of Girdin suppressed proliferation and reduced cell survival rate. Flow cytometry and DAPI staining results showed that knockdown of Girdin induced apoptosis in LN229 cells. Western blot results suggested that reduction of Gridin increased the level of Cytochrome C (Cyt-C) and Bad while decreased the expression of Bcl-2 and p-AKT. Moreover, subcutaneous mouse xenograft model was used to validate the role of Girdin in glioblastoma apoptosis. Consistently, in vivo assays showed that knockdown of Girdin inhibited the growth of the grafted tumor and increased the level of Cyt-C and Bad. These findings demonstrated that knockdown of Girdin may induce Bad expression and reduce Bcl-2 expression by inhibiting the activation of AKT, leading to the release of Cyt-C from mitochondria, thereby promoting glioblastoma cells apoptosis.

Performance of abbreviated protocols versus unenhanced MRI in detecting occult breast lesions of mammography in patients with dense breasts.

To assess the diagnostic ability of abbreviated protocols of MRI (AP-MRI) compared with unenhanced MRI (UE-MRI) in mammographically occult cancers in patients with dense breast tissue. The retrospective analysis consisted of 102 patients without positive findings on mammography who received preoperative MRI full diagnostic protocols (FDP) between January 2015 and December 2018. Two breast radiologists read the UE, AP, and FDP. The interpretation times were recorded. The comparisons of the sensitivity, specificity and area under the curve of each MRI protocol, and the sensitivity of these protocols in each subgroup of different size tumors used the Chi-square test. The paired sample t-test was used for evaluating the difference of reading time of the three protocols. Among 102 women, there were 68 cancers and two benign lesions in 64 patients and 38 patients had benign or negative findings. Both readers found the sensitivity and specificity of AP and UE-MRI were similar (p > 0.05), whereas compared with FDP, UE had lower sensitivity (Reader 1/Reader 2: p = 0.023, 0.004). For different lesion size groups, one of the readers found that AP and FDP had higher sensitivities than UE-MRI for detecting the lesions ≤ 10 mm in diameter (p = 0.041, p = 0.023). Compared with FDP, the average reading time of UE-MRI and AP was remarkably reduced (p < 0.001). AP-MRI had more advantages than UE-MRI to detect mammographically occult cancers, especially for breast tumors ≤ 10 mm in diameter.

Mechanisms and Kinetics Studies of Butylated Hydroxytoluene Degradation to Isobutene.

2,6-Di-tert-butyl-hydroxytotulene (BHT) is a widely used antioxidant in various fields. In this study, we explored comprehensively the mechanisms and kinetics of BHT degradation to produce isobutene using the density functional theory method. Furthermore, the intrinsic chemical reactivity of BHT was investigated using the electrostatic potential, average local ionization energy, and Fukui function, and the most likely reaction site with OH radical was predicted. Two initiation pathways of BHT with OH radicals were reported. The OH addition pathways at the C2 site of BHT was found more likely to occur than the pathways of H abstracts from the t-butyl group due to the lower energy barrier. Rate constants of two initiation pathways were calculated by transition state theory, and they were promoted by the temperature rise. Mayer bond order and localized molecular orbitals analysis were conducted to reveal the variation of the chemical bonds in the reaction process. The tertiary butyl radical that had been generated in the OH-addition reaction was more likely to generate isobutene with the participation of oxygen. Overall, this research could help to reveal the transformation mechanism of isobutene produced by BHT degradation.

Breast Cancer Patients With Positive Apical or Infraclavicular/Ipsilateral Supraclavicular Lymph Nodes Should Be Excluded in the Application of the Lymph Node Ratio System.

Aim: Increasing studies have demonstrated lymph node ratio (LNR) to be an accurate prognostic indicator in breast cancer and an alternative to pN staging; however, the AJCC-TNM staging system classified apical or infraclavicular/ipsilateral supraclavicular lymph node-positive (APN(+)) patients with a worse prognosis as the pN3 stage. Until now, different reports on LNR in breast cancer have ignored this possibility. Consequently, it is necessary to discuss the role of APN(+) patients in the LNR system to obtain a precise LNR that predicts the prognosis accurately. Materials and Methods: We collected data on 10,120 breast cancer patients, including 3,936 lymph node-positive patients (3,283 APN(-) and 653 APN(+) patients), who visited our hospital from 2007 to 2012. Then we applied X-tile analysis to calculate cut-off values and conduct survival analysis and multivariate analysis to evaluate patients' prognosis. Results: We confirmed that some APN(+) patients were mis-subgrouped according to previously reported LNR, indicating that APN(+) patients should be excluded in the application of LNR to predict prognosis. Then we applied X-tile analysis to calculate two cut-off values (0.15 and 0.34) for LNR-APN(-) patients and conducted survival analysis and found that LNR-APN(-) staging was superior to pN staging in predicting the prognosis of APN(-) breast cancer patients. Conclusion: From this study, we conclude that excluding APN(+) patients is the most necessary condition for effective implementation of the LNR system. LNR-APN(-) staging could be a more comprehensive approach in predicting prognosis and guiding clinicians to provide accurate and appropriate treatment.

Endocytic protein intersectin1-S shuttles into nucleus to suppress the DNA replication in breast cancer.

Breast cancer is the most common type of cancer worldwide. However, the well-known molecular biomarkers are not enough to meet the needs of precision medicine. In search for novel targets in this regard, we reported ITSN1 (intersectin1) as one of the candidates through mRNA microarray analysis. In the present study, we reported that endocytic protein ITSN1-S exists not only in the cytoplasm but also in nuclei of breast cancer cells. ITSN1-S' functional nuclear localization signal is within its residues 306-312. Its nuclear export signal (NES) resides within its SH3 domains. We also found, the interaction between the CC domain of nuclear ITSN1-S and the NT domain of nuclear DNA helicase II (NDH II) directly suppressed the DNA replication and nascent DNA synthesis by inhibiting the R-loops resolution in breast cancer cells. Furthermore, the interaction between the EH domains of cytoplasmic ITSN1-S and PI3KC2α inhibit cell migration and invasion by inactivating the PI3KC2α-AKT pathway. Our results were confirmed in both ITSN1 gene knockout cells and in vivo assays. Finally, our clinical data showed a potential application of the combined consideration of the cytoplasmic and nuclear ITSN1-S as an independent prognosis factor. In conclusion, our study revealed ITSN1-S' novel positioning in the nuclei of breast cancer cells, its function in suppressing DNA replication, and its potential application in improved breast cancer prognosis.

High Expression of Complement Component C7 Indicates Poor Prognosis of Breast Cancer and Is Insensitive to Taxane-Anthracycline Chemotherapy.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer worldwide. However, the well-known biomarkers are not enough to meet the needs of precision medicine. Novel targets are desirable and highly valuable for improved patient survival. In this regard, we identified complement component C7 as one of the candidates based on data from the OCOMINE database. METHODS: C7 expression was examined by immunohistochemistry in 331 cases of invasive ductal carcinoma (IDC), 45 cases of ductal carcinoma in situ (DCIS), and 52 cases of non-neoplastic tissues adjacent to tumor. Then, C7 expression was further confirmed by Western blot analysis based on IDC specimens and non-neoplastic breast specimens. The relationship between the C7 expression and prognosis of breast cancer patients was analyzed in order to investigate the function of C7 in breast cancer patients. Meanwhile, we also analyzed the relationship between the C7 expression and prognosis of 149 patients treated with conventional TE (taxane and anthracycline)-based chemotherapy. Then, a cohort of patients (22 cases) treated with TE neoadjuvant chemotherapy was used to further confirm the relationship between the C7 expression and TE-based chemosensitivity. RESULTS: In our present study, we reported for the first time that C7 was an independent prognostic factor of breast cancer and C7 expression of IDC tissues was higher than non-neoplastic tissues adjacent to tumor and DCIS. In a cohort of 331 IDC patients, high expression of C7 indicated poor prognosis especially in the triple negative subtype and luminal B subtype. Furthermore, C7 was also a promoting factor for triple negative subtype patients to develop bone metastasis. Meanwhile, we provided the first evidence that patients with high C7 expression were insensitive to TE (taxane and anthracycline)-based chemotherapy by analyzing a cohort of 149 patients treated with TE-based chemotherapy and another cohort of 22 patients treated with TE neoadjuvant chemotherapy. CONCLUSIONS: In summary, high expression of C7 may promote breast cancer development and might be insensitive to TE-based chemotherapy. Our present study laid a foundation to help clinicians improve the identification of patients for TE-based chemotherapy by C7 in the era of precision medicine.

Aquaporin 1 promotes sensitivity of anthracycline chemotherapy in breast cancer by inhibiting ß-catenin degradation to enhance TopoIIα activity.

Anthracyclines are a class of conventional and commonly used frontline chemotherapy drugs to treat breast cancer. However, the anthracycline-based regimens can only reduce breast cancer mortality by 20-30%. Furthermore, there is no appropriate biomarker for predicting responses to this kind of chemotherapy currently. Here we report our findings that may fill this gap by showing the AQP1 (Aquaporin1) protein as a potential response predictor in the anthracycline chemotherapy. We showed that breast cancer patients with a high level of AQP1 expression who underwent the anthracycline treatment had a better clinical outcome relative to those with a low level of AQP1 expression. In the exploration of the underlying mechanisms, we found that the AQP1 and glycogen synthase kinase-3ß (GSK3ß) competitively interacted with the 12 armadillo repeats of ß-catenin, followed by the inhibition of the ß-catenin degradation that led to ß-catenin's accumulation in the cytoplasm and nuclear translocation. The nuclear ß-catenin interacted with TopoIIα and enhanced TopoIIα's activity, which resulted in a high sensitivity of breast cancer cells to anthracyclines. We also found, the miR-320a-3p can attenuate the anthracycline's chemosensitivity by inhibiting the AQP1 expression. Taken together, our findings suggest the efficacy of AQP1 as a response predictor in the anthracycline chemotherapy. The application of our study includes, but is not limited to, facilitating screening of the most appropriate breast cancer patients (who have a high AQP1 expression) for better anthracycline chemotherapy and improved prognosis purposes.

Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response.

PURPOSE: Anterior gradient 3 (AGR3) belongs to human anterior gradient (AGR) family. The function of AGR3 on cancer remains unknown. This research aimed to investigate if AGR3 had prognostic values in invasive ductal carcinoma (IDC) of breast cancer and could promote tumor progression. MATERIALS AND METHODS: AGR3 expression was detected in breast benign lesions, ductal carcinoma in situ and IDC by immunohistochemistry analysis. AGR3's correlations with clinicopathological features and prognosis of IDC patients were analyzed. By cell function experiments, collagen gel droplet-embedded culture drug sensitivity test and cytotoxic analysis, AGR3's impacts on proliferation, invasion ability, and chemotherapeutic drug sensitivity of breast cancer cells were also detected. RESULTS: AGR3 was up-regulated in luminal subtype of histological grade I-II of IDC patients and positively correlated with high risks of recurrence and distant metastasis. AGR3 high expression could lead to bone or liver metastasis and predict poor prognosis of luminal B. In cell lines, AGR3 could promote proliferation and invasion ability of breast cancer cells which were consistent with clinical analysis. Besides, AGR3 could indicate poor prognosis of breast cancer patients treated with taxane but a favorable prognosis with 5-fluoropyrimidines. And breast cancer cells with AGR3 high expression were resistant to taxane but sensitive to 5-fluoropyrimidines. CONCLUSION: AGR3 might be a potential prognostic indicator in luminal B subtype of IDC patients of histological grade I-II. And patients with AGR3 high expression should be treated with chemotherapy regimens consisting of 5-fluoropyrimidines but no taxane.

Predicting kinase inhibitors using bioactivity matrix derived informer sets.

Prediction of compounds that are active against a desired biological target is a common step in drug discovery efforts. Virtual screening methods seek some active-enriched fraction of a library for experimental testing. Where data are too scarce to train supervised learning models for compound prioritization, initial screening must provide the necessary data. Commonly, such an initial library is selected on the basis of chemical diversity by some pseudo-random process (for example, the first few plates of a larger library) or by selecting an entire smaller library. These approaches may not produce a sufficient number or diversity of actives. An alternative approach is to select an informer set of screening compounds on the basis of chemogenomic information from previous testing of compounds against a large number of targets. We compare different ways of using chemogenomic data to choose a small informer set of compounds based on previously measured bioactivity data. We develop this Informer-Based-Ranking (IBR) approach using the Published Kinase Inhibitor Sets (PKIS) as the chemogenomic data to select the informer sets. We test the informer compounds on a target that is not part of the chemogenomic data, then predict the activity of the remaining compounds based on the experimental informer data and the chemogenomic data. Through new chemical screening experiments, we demonstrate the utility of IBR strategies in a prospective test on three kinase targets not included in the PKIS.

Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression.

Intersectin1 (ITSN1) contains two isoforms: ITSN1-S and ITSN1-L, which is highly regulated by alternative splicing. However, the alteration of alternative splicing and its importance in cancer is still unknown. In this study, our transcriptome analysis by using a large glioma cohort indicated the two isoforms exerted opposite function in glioma progression. Our previous results had shown ITSN1-S could promote glioma development; however, the function of ITSN1-L remained unknown. In this study, we first confirmed that ITSN1-L exerted an inhibitory role in glioma progression both in vivo and in vitro, which was contrary to the function of ITSN1-S. In additional, we also elucidated the mechanisms of ITSN1-L in inhibiting tumor progression. First, we revealed ITSN1-L could interact with α-tubulin to promote HDAC6-dependent deacetylation of ac-tubulin leading to decreased cell motility. Second, ITSN1-L could attenuate cell-substrate adhesion through FAK/integrin ß3 pathway. Third, ITSN1-L was able to strengthen cell-cell adhesion by upregulating N-cadherin expression and its re-localization to membrane by ANXA2 and TUBB3/TUBB4. In conclusion, we found for the first time that two isoforms produced by alternative splicing exerted opposite functions in glioma development. Therefore, upregulation of ITSN1-L expression as well as downregulation of ITSN1-S expression probably was a better strategy in glioma treatment. Our present study laid a foundation for the importance of alternative splicing in glioma progression and raised the possibility of controlling glioma development completely at an alternative splicing level to be a more effective strategy.

Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer.

Girdin is an actin-binding protein playing key roles in the development of various carcinomas. Although online tools have predicted nuclear localization of girdin with a high probability, convincing proof has rarely been provided until now. The purpose of this study was to discover girdin's precise subcellular distribution and the potential prognostic value corresponding to its localization. The subcellular distribution of girdin was detected in a human breast cancer cell line and in >800 samples of human breast tissue by clinical pathologic analysis. In this study, we discovered for the first time that girdin could attach to chromatin and interact with topoisomerase-IIα in nucleus. Cytoplasmic and nuclear girdin exhibited different roles in prognosis of breast cancer: cytoplasmic girdin expression was an independent prognostic factor for progression-free survival (PFS), whereas nuclear girdin expression was an independent prognostic factor for overall survival (OS). More important, combination cytoplasmic and nuclear girdin was an independent prognosis factor of both OS and PFS. In conclusion, our research results strongly recommend combination analysis of cytoplasmic and nuclear girdin for a precise prognostic prediction in breast cancer.-Zhang, H., Yu, F., Qin, F., Shao, Y., Chong, W., Guo, Z., Liu, X., Fu, L., Gu, F., Ma, Y. Combination of cytoplasmic and nuclear girdin expression is an independent prognosis factor of breast cancer.

Combination of AQP1 and ß-catenin expression is an independent prognosis factor in astrocytoma patients.

Previous research usually focused on single protein or gene in tumor development, actually highly heterogeneous nature and different signaling pathways largely contribute to tumor progression and tumor patients' outcomes. Therefore, using combinatorial biomarkers to evaluate the prognostic features and guide management is gradually accepted and urgently needed. ß-catenin is a well-known crucial factor in astrocytoma progression and it is involved in aquaporin1 (AQP1) mediated cell migration. In this study, we revealed the function of AQP1 in astrocytoma progression and provided the first clinical evidence that AQP1 expression was positively correlated with ß-catenin. Furthermore, we proved the functional role of AQP1/ß-catenin pathway in astrocytoma progression. More importantly, we discovered that combination of AQP1 and ß-catenin expression was an independent prognosis factor for astrocytoma patients and it was a better survival predictor than either AQP1 or ß-catenin alone. In conclusion, our study provided a novel more precise prognostication for predicting astrocytoma prognosis based on combinatorial analysis of AQP1 and ß-catenin expression.

Machine Learning Consensus Scoring Improves Performance Across Targets in Structure-Based Virtual Screening.

In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target.

Effect of dihydropyrimidine dehydrogenase single nucleotide polymorphisms on prognosis of breast cancer patients with chemotherapy.

Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. DPD (dihydropyrimidine dehydrogenase, encoded by DPYD gene) is the initial and rate-limiting enzyme of metabolic pathway of fluoropyrimidines, and fluoropyrimidines are common used drug therapies for breast cancer. Previous studies on DPYD polymorphism were mainly focused on its association with fluoropyrimidines toxicity. In our present study, 5 DPYD single nucleotide polymorphisms status was detected from tumor tissues of 331 invasive breast cancer patients using standard techniques. We for the first time investigated the prognostic significance of DPYD polymorphisms in breast cancer. We demonstrated non-luminal breast cancer patients carrying DPYD c.1627A>G AG/GG treated with fluoropyrimidine-based regimen presented a shorter overall survival and progression-free survival than carriers treated with non-fluoropyrimidine regimen. However, non-luminal DPYD c.1627A>G AG/GG carriers treated with TE (taxane and anthracycline)-based regimen showed a better prognosis compared with carriers treated with non-TE regimen. Our results suggested TE-based chemotherapy was a suitable regimen for non-luminal patients with DPYD c.1627A>G AG/GG genotype and fluoropyrimidine-based regimen should not be recommended for those patients. Our findings provided a novel strategy, which will guide clinicians to choose more precise chemotherapy treatment for breast cancer patients.

Expression of aquaporin1, a water channel protein, in cytoplasm is negatively correlated with prognosis of breast cancer patients.

Aquaporin1 (AQP1) belongs to a highly conserved family of aquaporin proteins which facilitate water flux across cell membranes. Although emerging evidences indicated the cytoplasm was important for AQP1 localization, the function of AQP1 corresponding to its cytoplasmic distribution has rarely been explored until present. In our clinical study, we reported for the first time that AQP1 was localized dominantly in the cytoplasm of cancer cells of invasive breast cancer patients and cytoplasmic AQP1 was an independent prognostic factor. High expression of AQP1 indicated a shorter survival, especially in luminal subtype. Moreover, in line with our findings in clinic, cytoplasmic expression of AQP1 was further validated in both primary cultured breast cancer cells and AQP1 over-expressing cell lines, in which the functional importance of cytoplasmic AQP1 was confirmed in vitro. In conclusion, our study provided the first evidence that cytoplasmic expression of AQP1 promoted breast cancer progression and it could be a potential prognostic biomarker for breast cancer.

Low expression of BMPRIB indicates poor prognosis of breast cancer and is insensitive to taxane-anthracycline chemotherapy.

Bone morphogenetic protein receptor type IB (BMPRIB) is one osteogenesis factor, which function in breast cancer has been rarely explored until recently. In the clinical study presented here, involving a cohort of 368 invasive ductal carcinoma (IDC) patients, we identified that patients with low expression of BMPRIB exhibited poor prognosis, especially in the luminal B subtype. We also provided the first piece of evidence that low level of BMPRIB was a promoting factor for breast cancer patients to develop bone metastasis, but not lung, liver or brain. The first of its kind, we reported that patients with high expression of BMPRIB exhibited favorable prognosis by a retrospective analysis consisting of 168 patients treated with TE (taxane and anthracycline) regimens. And the patients with high expression of BMPRIB were more sensitive to TE regimens in the detection of 32 paired pre-neoadjuvant and post-neoadjuvant specimens. Overall, our study concluded that low expression of BMPRIB indicated poor prognosis of breast cancer and was insensitive to taxane-anthracycline chemotherapy. Our findings also lay a foundation to help clinicians improve identification of patients for TE regimens by BMPRIB in the era of precision medicine.

Low Expression of Slit2 and Robo1 is Associated with Poor Prognosis and Brain-specific Metastasis of Breast Cancer Patients.

Brain metastasis is a significant unmet clinical problem in breast cancer treatment. It is always associated with poor prognosis and high morbidity. Recently, Slit2/Robo1 pathway has been demonstrated to be involved in the progression of breast carcinoma. However, until present, there are no convincing reports that suggest whether the Slit2/Robo1 axis has any role in brain metastasis of breast cancer. In this study, we investigated the correlation between Slit2/Robo1 signaling and breast cancer brain metastasis for the first time. Our results demonstrated that (1) Invasive ductal carcinoma patients with low expression of Slit2 or Robo1 exhibited worse prognosis and brain-specific metastasis, but not liver, bone or lung. (2) Lower expression of Slit2 and Robo1 were observed in patients with brain metastasis, especially in their brain metastasis tumors, compared with patients without brain metastasis. (3) The interval from diagnosis of breast cancer to brain metastasis and brain metastasis to death were both much shorter in patients with low expression of Slit2 or Robo1 compared with the high expression group. Overall, our findings indicated that Slit2/Robo1 axis possibly be regarded as a significant clinical parameter for predicting brain metastasis in breast cancer patients.

Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation.

Glioblastomas, the most aggressive form of primary brain tumors with a tendency to invade surrounding healthy brain tissues, remains an incurable disease. Intersectin (ITSN) is a multidomain adapter protein implicated in endocytosis, exocytosis, and multiple signaling pathways. Prior research of ours has shown intersectin1-S (ITSN1-S) is critical for the migration and invasion of glioma cells by regulating several key proteins. In this study, we established ITSN1-S expression patterns in human tumor tissues. We discovered that ITSN1-S expression was positively correlated with histological grade of gliomas and with poor patient prognosis. We also found that the expression of ITSN1-S protein was essential to glioblastoma cell proliferation. Furthermore, through a series of expression constructs encoding different ITSN1-S domains, we identified the critical roles of ITSN1-S SH3 domains in the regulation of cell proliferation. This study also demonstrates evidence suggesting that the regulation of ITSN1-S on glioblastoma cells proliferation is through the Raf/MEK/ERK pathway. In conclusion, this study suggests critical roles of ITSN1-S in malignant glioma proliferation, indicating a potential usage of ITSN1-S in the therapeutic intervention as a novel molecular target.