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Trastuzumab is the only approved targeted drug for first-line treatment of HER2-positive advanced gastric cancer, but the high rate of primary resistance and rapid emergence of secondary resistance limit its clinical benefits. We found that trastuzumab-resistant (TR) gastric cancer cells exhibited high glycolytic activity, which was controlled by hexokinase 2 (HK2)-dependent glycolysis with a circadian pattern [higher at zeitgeber time (ZT) 6, lower at ZT18]. Mechanistically, HK2 circadian oscillation was regulated by a transcriptional complex composed of PPARγ and the core clock gene PER1. In vivo and in vitro experiments demonstrated that silencing PER1 disrupted the circadian rhythm of PER1–HK2 and reversed trastuzumab resistance. Moreover, metformin, which inhibits glycolysis and PER1, combined with trastuzumab at ZT6, significantly improved trastuzumab efficacy in gastric cancer. Collectively, these data introduce the circadian clock into trastuzumab therapy and propose a potentially effective chronotherapy strategy to reverse trastuzumab resistance in gastric cancer. Significance: In trastuzumab-resistant HER2-positive gastric cancer, glycolysis fluctuates with a circadian oscillation regulated by the BMAL1–CLOCK–PER1–HK2 axis, which can be disrupted with a metformin-based chronotherapy to overcome trastuzumab resistance.

Purpose: Epidermal growth factor receptor (EGFR) mutation is the most common target for precision treatment in metastatic lung adenocarcinoma. We investigated the predictive role of 18F-FDG PET/CT and clinicopathological features for EGFR mutations in lung adenocarcinoma with bone metastasis. Methods: Seventy-five lung adenocarcinoma patients with histologically confirmed bone metastasis were included. They all received EGFR status test and PET/CT before systemic treatment. The differences of maximum standardized uptake value (SUVmax) in primary tumor (pSUVmax), regional lymph node (nSUVmax) and bone metastasis (bmSUVmax) between different EGFR status groups were compared, alongside with common clinicopathological features. Multivariate logistic regression analysis was performed to evaluate predictors of EGFR mutations. Results: EGFR mutations were found in 37 patients (49.3%). EGFR mutations were more common in females, non-smokers, expression of Thyroid Transcription Factor-1 (TTF-1) and NaspinA. Low bmSUVmax was significantly associated with EGFR mutations, while no significant difference was observed in pSUVmax and nSUVmax. Multivariate analysis showed that bmSUVmax ≤7, non-smoking, expression of TTF-1 were predictors of EGFR mutations. The area under the curve (AUC) of receiver operating characteristic (ROC) curve was 0.84 for the combination of the three factors. Conclusion: Low bmSUVmax is more frequently in EGFR mutations, and bmSUVmax is an independent predictor of EGFR mutations. Combining bmSUVmax with other clinicopathological features could forecast the EGFR status in lung adenocarcinoma with unavailable EGFR gene testing.

Purpose: We evaluated the imaging and clinical features for discriminating the possibility of metastasis among FDG-avid bone lesions in 18F-FDG PET/CT in patients who have received bone biopsy. Methods: The retrospective study included patients who underwent both 18F-FDG PET/CT and bone biopsy for FDG-avid bone lesions. Bone lesions maximum standardized uptake value (SUVmax), CT findings, alongside with common clinical features were analyzed. Results: From the 338 patients enrolled in the final study, all of them were received bone biopsy. Biopsies confirm metastasis in 256 cases (75.74%) and benign tissue in 82 cases (24.26%). Metastasis group had higher bone SUVmax than benign group (median 7.9 vs 4.5, p

Purpose To quantitatively evaluate the effect of preexisting diabetes mellitus (DM) on the outcomes of patients with non-small-cell lung cancer (NSCLC). Materials and methods Observational studies comparing the prognosis of NSCLC patients with and without diabetes were identified from PubMed, EMBASE, and The Cochrane Central Register of Controlled Trials (CENTRAL). We searched for studies that published in English from inception to March 30, 2019, using search terms related to diabetes and NSCLC. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated by a random-effect model and subgroup analyses were performed. Results In all, 17 of 1475 identified studies were finally included in the meta-analysis. The result revealed that preexisting diabetes had a significantly negative impact on the overall survival (OS) of patients with NSCLC (HR: 1.31, 95% CI: 1.12-1.54), especially in patients undergoing surgical treatment (HR: 1.46, 95% CI: 1.02-2.09) in comparison with those receiving only non-surgical treatment (HR: 1.33, 95% CI: 0.87-2.03). In addition, preexisting diabetes was more likely to be associated with a worse prognosis among Asian NSCLC patients than Western patients. Sensitivity analysis indicated that the main result was robust, and no evidence of publication bias was found. Conclusion Preexisting DM has a negative impact on diabetic NSCLC patients' prognosis.

BackgroundIdentified as a hallmark of cancer, the dysregulated cell cycle progression plays an important role in the promotion and progression of lung adenocarcinoma (LUAD). However, the genomic and microenvironment differences between cell cycle progression pathway altered/non-altered LUAD patients remain to be elucidated.Materials and MethodsData of this study were obtained from The Cancer Genome Atlas (TCGA), including simple nucleotide variation, copy number variation (CNV), RNA-seq gene expression, miRNA expression, survival, and clinical information. Besides, 34 LUAD samples from our institution were used as a validation cohort. Differentially expressed genes (DEGs), enrichment analysis, and immune cell infiltration were detected. At last, we built a LASSO-binary Logistic regression model to predict the cell-cycle-related gene mutation (CDKN2A, CCND1, CDK4, CCNE1, and RB1) in LUAD patients and further verified it in the samples from our institution.ResultsBased on the cell cycle progression pathway status, the LUAD patients were divided into the mutation (n=322) and wild (n=46) groups. Compared to the wild group, the mutation group had a higher mutational load and CNV. Among the 16684 protein-coding genes analyzed, 302 were upregulated, and 354 were downregulated in the mutation group. Enrichment analysis indicated that these DEGs were closely related to metabolism items. After performing immune cell infiltration analysis of 22 immune cells, we found the proportion of 5 immune cells such as monocytes (PConclusionThe genomic and microenvironment characteristics differed between the cell cycle progression pathway altered/non-altered patients with LUAD. Our findings may provide new insight into personalized treatment for LUAD patients.

Breast cancer is a common cancer among women in the world. However, its pathogenesis is still to be determined. The role and molecular mechanism of Nucleosome Assembly Protein 1 Like 1 (NAP1L1) in breast cancer have not been reported. Elucidation of molecular mechanism might provide a novel therapeutic target for breast cancer treatment.A bioinformatics analysis was conducted to determine the differential expression of NAP1L1 in breast cancer and find the potential biomarker that interacts with NAP1L1 and hepatoma-derived growth factor (HDGF). The expression of NAP1L1 in tissues was detected by using immunohistochemistry. Breast cancer cells were transfected with the corresponding lentiviral particles and siRNA. The efficiency of transfection was measured by RT-qPCR and western blotting. Then, MTT, Edu, plate clone formation, and subcutaneous tumorigenesis in nude mice were used to detect the cell proliferation in breast cancer. Furthermore, coimmunoprecipitation (Co-IP) assay and confocal microscopy were performed to explore the detailed molecular mechanism of NAP1L1 in breast cancer.In this study, NAP1L1 protein was upregulated based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Consistent with the prediction, immunohistochemistry staining showed that NAP1L1 protein expression was significantly increased in breast cancer tissues. Its elevated expression was an unfavorable factor for breast cancer clinical progression and poor prognosis. Stably or transiently knocking down NAP1L1 reduced the cell growth in vivo and in vitro via repressing the cell cycle signal in breast cancer. Furthermore, the molecular basis of NAP1L1-induced cell cycle signal was further studied. NAP1L1 interacted with the HDGF, an oncogenic factor for tumors, and the latter subsequently recruited the key oncogenic transcription factor c-Jun, which finally induced the expression of cell cycle promoter Cyclin D1(CCND1) and thus the cell growth of breast cancer.Our data demonstrated that NAP1L1 functions as a potential oncogene via interacting with HDGF to recruit c-Jun in breast cancer.

Background Breast cancer is a common cancer among women in the world. However, its pathogenesis is still to be determined. The role and molecular mechanism of Nucleosome Assembly Protein 1 Like 1 (NAP1L1) in breast cancer have not been reported. Elucidation of molecular mechanism might provide a novel therapeutic target for breast cancer treatment. Methods A bioinformatics analysis was conducted to determine the differential expression of NAP1L1 in breast cancer and find the potential biomarker that interacts with NAP1L1 and hepatoma-derived growth factor (HDGF). The expression of NAP1L1 in tissues was detected by using immunohistochemistry. Breast cancer cells were transfected with the corresponding lentiviral particles and siRNA. The efficiency of transfection was measured by RT-qPCR and western blotting. Then, MTT, Edu, plate clone formation, and subcutaneous tumorigenesis in nude mice were used to detect the cell proliferation in breast cancer. Furthermore, coimmunoprecipitation (Co-IP) assay and confocal microscopy were performed to explore the detailed molecular mechanism of NAP1L1 in breast cancer. Results In this study, NAP1L1 protein was upregulated based on the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Consistent with the prediction, immunohistochemistry staining showed that NAP1L1 protein expression was significantly increased in breast cancer tissues. Its elevated expression was an unfavorable factor for breast cancer clinical progression and poor prognosis. Stably or transiently knocking down NAP1L1 reduced the cell growth in vivo and in vitro via repressing the cell cycle signal in breast cancer. Furthermore, the molecular basis of NAP1L1-induced cell cycle signal was further studied. NAP1L1 interacted with the HDGF, an oncogenic factor for tumors, and the latter subsequently recruited the key oncogenic transcription factor c-Jun, which finally induced the expression of cell cycle promoter Cyclin D1(CCND1) and thus the cell growth of breast cancer. Conclusions Our data demonstrated that NAP1L1 functions as a potential oncogene via interacting with HDGF to recruit c-Jun in breast cancer.

Aims: To assess the efficacy and safety of adjuvant capecitabine in early breast cancer patients. Methods: A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and toxicity of capecitabine as adjuvant therapy in early breast cancer patients. Results: Six studies were eligible and included a total of 6941 patients. Disease-free survival (hazard ratio = 0.79; 95% CI = 0.71–0.88; p

Breast cancer is the most common malignancy in women, and its incidence increases annually. Traditional therapies have several side effects, leading to the urgent need to explore new smart drug-delivery systems and find new therapeutic strategies. Graphene-based nanomaterials (GBNs) are potential drug carriers due to their target selectivity, easy functionalization, chemosensitization and high drug-loading capacity. Previous studies have revealed that GBNs play an important role in fighting breast cancer. Here, we have summarized the superior properties of GBNs and modifications to shape GBNs for improved function. Then, we focus on the applications of GBNs in breast cancer treatment, including drug delivery, gene therapy, phototherapy, and magnetothermal therapy (MTT), and as a platform to combine multiple therapies. Their advantages in enhancing therapeutic effects, reducing the toxicity of chemotherapeutic drugs, overcoming multidrug resistance (MDR) and inhibiting tumor metastasis are highlighted. This review aims to help evaluate GBNs as therapeutic strategies and provide additional novel ideas for their application in breast cancer therapy.

Background Lymph node ratio (LNR), defined as the ratio of the number of positive lymph nodes to the total of all resected nodes, has been reported to be a predictor of survival of patients with several types of cancer. However, the prognostic value of LNR and other factors in patients with resected N2 stage lung squamous cell carcinoma has never been considered. Methods Data from 1778 patients with resected N2 stage lung squamous cell carcinoma were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of LNR was identified by X-tile. A multivariable Cox model and corresponding nomogram were constructed to predict overall survival (OS) and cancer-specific survival (CSS). Both the cutoff value of LNR and the model were further validated in 146 similar patients treated in Zhongshan Hospital. Heat maps were created to visualize the distribution of LNR and the number of positive lymph nodes with the predicted survival probabilities. Results The optimal cutoff value for LNR was identified as 0.42. Multivariable analysis showed that age, sex, tumor laterality, type of surgery, T stage, chemotherapy and LNR were independently correlated with OS. Harrell's C-index of the nomogram (0.64) was significantly higher than the index of the T stage-based model (0.54). Calibration curves showed good agreement between predicted and observed survival probabilities. The robustness of the model was also demonstrated by external validation. Conclusion LNR less than 0.42 was associated with improved OS and CSS for patients with resected N2 stage lung squamous cell carcinoma.

Background One year of adjuvant trastuzumab treatment is the standard of care for early stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients; however, controversy remains regarding the optimal schedule of trastuzumab because the selection of the 1-year schedule was arbitrary. After the remarkable results of the PERSEPHONE trial as well as the updated final results of the PHARE trial, we performed an updated meta-analysis to reassess the efficacy and safety of shorter durations of trastuzumab. Methods A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and cardiotoxicity of shorter-duration and standard 1-year trastuzumab treatment. The hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS), and the odds ratios (ORs) of cardiac events were also estimated and pooled. Results Six studies were eligible, including a total of 11,496 patients. Both DFS (HR = 1.13; 95% confidence interval [CI] = 1.03–1.25; p = 0.01) and OS (HR = 1.16; 95% CI = 1.01–1.32; p = 0.03) were significantly improved with conventional 1-year trastuzumab treatment compared with shorter treatments. The more pronounced survival benefits observed in patients with negative estrogen receptor (ER) tumor and nodal involvement should be interpreted cautiously because of the lack of interaction between the survival benefit and ER, as well as the nodal status (interaction test, ER status: p = 0.26; nodal status: p = 0.60). One year of trastuzumab treatment resulted in a substantial DFS benefit compared with shorter schedules when administered concurrently with chemotherapy (HR = 1.22; 95% CI = 1.09–1.38; p = 0.0008; p = 0.02 for the interaction test). Patients in the shorter duration group experienced significantly fewer cardiac events (OR = 0.52; 95% CI = 0.43–0.62; p Conclusions Though correlated with an increasing risk of cardiotoxicity, 1 year of adjuvant trastuzumab treatment conferred substantial survival benefits and should remain as the preferred treatment for early stage HER2-positive breast cancer. Shorter durations of trastuzumab may serve as an alternative choice for patients with cardiac disease and those at lower risk of recurrence.

Aim. This study is aimed at building a risk model based on the genes that significantly altered the proliferation of lung adenocarcinoma cells and exploring the underlying mechanisms. Methods. The data of 60 lung adenocarcinoma cell lines in the Cancer Dependency Map (Depmap) were used to identify the genes whose knockout led to dramatical acceleration or deacceleration of cell proliferation. Then, univariate Cox regression was performed using the survival data of 497 patients with lung adenocarcinoma in The Cancer Genome Atlas (TCGA). The least absolute shrinkage and selection operator (LASSO) model was used to construct a risk prediction score model. Patients with lung adenocarcinoma from TCGA were classified into high- or low-risk groups based on the scores. The differences in clinicopathologic, genomic, and immune characteristics between the two groups were analyzed. The prognosis of the genes in the model was verified with immunohistochemical staining in 100 samples from the Department of Thoracic Surgery, Zhongshan Hospital, and the alteration in the proliferation rate was checked after these genes were knocked down in lung adenocarcinoma cells (A549 and H358). Results. A total of 55 genes were found to be significantly related to survival by combined methods, which were crucial to tumor progression in functional enrichment analysis. A six-gene-based risk prediction score, including the proteasome subunit beta type-6 (PSMB6), the heat shock protein family A member 9 (HSPA9), the deoxyuridine triphosphatase (DUT), the cyclin-dependent kinase 7 (CDK7), the polo-like kinases 1 (PLK1), and the folate receptor beta 2 (FOLR2), was built using the LASSO method. The high-risk group classified with the score model was characterized by poor overall survival (OS), immune infiltration, and relatively higher mutation load. A total of 9864 differentially expressed genes and 138 differentially expressed miRNAs were found between the two groups. Also, a nomogram comparing score model, age, and the stage was built to predict OS for patients with lung adenocarcinoma. Using immunohistochemistry, the expression levels of PSMB6, HSPA9, DUT, CDK7, and PLK1 were found to be higher in lung adenocarcinoma tissues of patients, while the expression of FOLR2 was low, which was consistent with survival prediction. The knockdown of PSMB6 and HSPA9 by siRNA significantly downregulated the proliferation of A549 and H358 cells. Conclusion. The proposed score model may function as a promising risk prediction tool for patients with lung adenocarcinoma and provide insights into the molecular regulation mechanism of lung adenocarcinoma.

Background Alterations in serum creatinine levels delay the identification of severe cardiac surgery‐associated acute kidney injury. To provide timely diagnosis, novel predictive tools should be investigated. Methods and Results This prospective observational study consists of a screening cohort (n=204) and a validation cohort (n=198) from 2 centers from our hospital. Thirty‐two inflammatory cytokines were measured via a multiplex cytokine assay. Least absolute shrinkage and selection operator regression was conducted to select the cytokine signatures of severe cardiac surgery‐associated acute kidney injury. Afterwards, the significant candidates including interferon‐γ, interleukin‐16, and MIP‐1α (macrophage inflammatory protein‐1 alpha) were integrated into the logistic regression model to construct a predictive model. The predictive accuracy of the model was evaluated in these 2 cohorts. The cytokine‐based model yielded decent performance in both the screening (C‐statistic: 0.87, Brier 0.10) and validation cohorts (C‐statistic: 0.86, Brier 0.11). Decision curve analysis revealed that the cytokine‐based model had a superior net benefit over both the clinical factor‐based model and the established plasma biomarker‐based model for predicting severe acute kidney injury. In addition, elevated concentrations of each cytokine were associated with longer mechanical ventilation times, intensive care unit stays, and hospital stays. They strongly predicted the risk of composite events (defined as treatment with renal replacement therapy and/or in‐hospital death) (OR of the fourth versus the first quartile [95% CI]: interferon‐γ, 27.78 [3.61–213.84], interleukin‐16, 38.07 [4.98–291.07], and MIP‐1α, 9.13 [2.84–29.33]). Conclusions Our study developed and validated a promising blood cytokine‐based model for predicting severe acute kidney injury after cardiac surgery and identified prognostic biomarkers for assisting in outcome risk stratification.

Bone metastasis (BM) dramatically reduces the quality of life and life expectancy in lung adenocarcinoma (LUAD) patients. There is an urgent need to identify potential biomarkers for application in the treatment of this deadly disease. We compared patient BM, LUAD, and para-LUAD tissues using proteomic analysis and identified aldehyde dehydrogenase 2 (ALDH2), which can detoxify acetaldehyde to acetic acid, as one of the key regulators in lung tumor metastasis. Both the mRNA and protein levels of ALDH2 were significantly lower in tumor tissues than in normal tissues and were lowest in BM tissues with increased migratory capacity. Also, ALDH2 was upregulated following treatment with 5-azacitidine, a DNA methyltransferase inhibitor, in H1299, H460, and HCC827 cells. Further, we identified a potential methylated CpG island 3, with the longest methylated CpG island area in ALDH2, and performed bisulfite genomic sequencing of these sites. An average of 78.18% of the sites may be methylated in CpG island 3. Knockdown of DNA (cytosine-5)-methyltransferase 3A (DNMT3A) and methylated CpG binding protein 4 (MBD4) upregulated ALDH2 expression. ALDH2 functions as a mitogen-activated protein kinase (MAPK) upstream to inhibit cell proliferation and migration, promote cell apoptosis, and alter the epithelial-mesenchymal transition (EMT) by elevating E-cadherin and attenuating vimentin. Cell proliferation and migration were inhibited after the addition of the JNK inhibitor SP600125. In the multivariate analysis, M stage (p = 0.003), ALDH2 (p = 0.008), and phospho-c-Jun N-terminal kinase (p-JNK) (p = 0.027) expression were independent prognostic factors for overall survival in patients with BM. In vivo experiments also showed that ALDH2 expression could suppress tumor formation. In summary, we found that ALDH2 expression is a prognostic factor for BM in LUAD and that DNMT3A and MBD4 repression of ALDH2 via a MAPK-dependent pathway alters the EMT process, indicating that these proteins could act as potential biomarkers or therapeutic targets for LUAD metastasis.

Colorectal cancer (CRC)-associated senescent fibroblasts may play a crucial role in tumor progression, but the mechanism remains unclear. In order to solve this complicated problem, we randomly collected 16 patients with CRC, who had been treated with oxaliplatin and capecitabine (XELOX). Hematoxylin-eosin (HE) staining revealed that the tumor-stroma ratio (TSR) of CRC was affected by XELOX treatment. Immunohistochemistry (IHC) and senescence-associated β-galactosidase (SAβG) staining were used to verify a stable model of senescent fibroblasts. IHC analysis showed that high expression levels of galactosylceramidase (GALC) and significant senescence-associated β-galactosidase (SAβG) staining were associated with CRC patient survival. We observed that fibroblasts overexpressing GALC underwent cell cycle arrest. Changes in cell morphology and cell cycle characteristics were accompanied by the upregulation of the p16, p21, and p53 gene, and the downregulation of hTERT expression. In a co-culture system, fibroblasts overexpressing GALC significantly increased the proliferation of CRC cells. Transmission electron microscopy (TEM) analysis confirmed that GALC overexpression fibroblasts co-cultured with CRC caused changes in CRC cell morphology. The aging fibroblast co-culture group (70%) had a higher migration ability. In vivo experiments and transcriptomics analysis were performed to verify the effect of senescent fibroblasts on tumor formation and to identify the potential mechanisms for the above results. We found that a high expression of ATF3 was related to good survival rates. However, a high expression of KIAA0907 was bad for survival rates (p < 0.05). The knockdown of ATF3 can promote cell proliferation, migration, and clonogenic assays, while downregulation of KIAA0907 inhibits cell proliferation, migration, and clonogenic assays. The results demonstrate that senescent fibroblasts with a high level of GALC regulated several aspects of the tumor growth process, including migration and invasion.

Despite recent advances in targeted and immune‐based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. First, two‐dimensional gel electrophoresis (2‐DE) was used to identify proteins that were differentially expressed in LUAD with BM, and then matrix‐assisted laser desorption/ionization time of flight mass spectrometry (MALDI‐TOF‐MS) was used to identify these proteins. Second, the Cancer Genome Atlas (TCGA) was used to identify mutations in these differentially expressed proteins and Kaplan–Meier plotter (KM Plotter) was used to generate survival curves for the analyzed cases. Immunohistochemistry (IHC) was used to check the expression of proteins in 28 patients with BM and nine patients with LUAD. Lastly, the results were analyzed with respect to clinical features and patient's follow‐up. We identified a number of matched proteins from 2‐DE. High expression of enolase 1 (ENO1) (HR = 1.67, logrank P = 1.9E‐05), ribosomal protein lateral stalk subunit P2 (RPLP2) (HR = 1.77, logrank P = 2.9e‐06), and NME/NM23 nucleoside diphosphate kinase 2 (NME1‐NME2) (HR = 2.65, logrank P = 3.9E‐15) was all significantly associated with poor survival (P

Capecitabine has consistently demonstrated high efficacy and acceptable tolerability in salvage chemotherapy for advanced breast cancer. However, there remains no consensus on its role in adjuvant chemotherapy for early breast cancer (EBC). To estimate the value of capecitabine-based combination adjuvant treatment in EBC, eight randomized controlled trials with 14,072 participants were analyzed. The efficacy and safety outcomes included disease-free survival (DFS), overall survival (OS), relapse, breast cancer-specific survival (BCSS), and grades 3‐5 adverse events. Capecitabine-based combination adjuvant chemotherapy demonstrated a 16% increase in BCSS (HR = 0.84, 95% CI = 0.71‐0.98, p = 0.03) in the overall analysis and a 22% improvement in DFS (HR = 0.78, 95% CI = 0.64‐0.96, p = 0.02) in the hormone receptor-negative (HR−) subgroup. However, there were no significant differences in DFS (HR = 0.96, 95% CI = 0.89‐1.05, p = 0.38), OS (HR = 0.91, 95% CI = 0.82‐1.00, p = 0.06), or relapse between capecitabine-based and capecitabine-free combination adjuvant chemotherapy. Analogous results were observed in the subgroup analyses of HR+, HER2−, HER2+, and triple-negative EBC. Regarding safety, reduced myelosuppression and hand‐foot syndrome development were observed in capecitabine-treated patients. Capecitabine-based combination adjuvant chemotherapy might provide some BCSS benefit compared with capecitabine-free regimens in EBC, but the absolute survival gain is small, and the survival benefit appears to be restricted to patients with HR− EBC, which may indicate a target population for capecitabine-based combination adjuvant chemotherapy.

Purpose: To examine diagnostic performance of qualitative shear wave elastography (SWE) for evaluation of status of axillary lymph nodes (ALN) in comparison with conventional ultrasonograghy (US) and quantitative SWE parameters.Methods: A total of 118 patients were enrolled, who were all scheduled for breast cancer surgery and core needle biopsy. Conventional US and SWE were performed before biopsy. Based on qualitative evaluation of each ALN, the SWE images were classified into four color patterns: Color Pattern 1: homogeneous; Color Pattern 2: filling defect within lymph node (LN); Color Pattern 3: homogeneous within LN with a localized colored area at the margin; and Color Pattern 4: filling defect within LN with a localized colored area at the margin. The diagnostic performances of the three methods were compared.Results: There were 60 metastatic nodes and 61 benign nodes in the 121 ALNs. Benign ALNs were presented as Color Pattern 1 while metastatic ALNs usually were presented as Color Pattern 2 to 4 (p < 0.05). The AUC of qualitative SWE classification was 0.983, higher than that of quantitative SWE parameters and conventional US (p

Aim: To explore the correlation between hematocrit (Hct) and response to neoadjuvant chemotherapy in breast cancer. Methods: The baseline clinicopathologic variables of included patients were retrospectively reviewed. Binary logistic regression analysis was performed to assess the predictive value of Hct on objective response. Results: Patients in Hct

Background: Owing to the need for effective and tolerable new regimens for the treatment of patients with metastatic breast cancer (MBC) previously treated with anthracyclines and/or taxanes, we aimed to assess the activity and safety of the gemcitabine plus capecitabine combination chemotherapy. Methods: Sixty-four patients were enrolled. Treatment consisted of gemcitabine 1,000 mg/m2 intravenously on days 1 and 8, plus oral capecitabine at 1,250 mg/m2 twice daily on days 1-14. The primary end point was the overall response rate (ORR). Secondary objectives included the disease control rate (DCR), overall survival (OS), progression-free survival (PFS), toxicity, and predictive factors. Results: In the 64 patients, the ORR and DCR was 28.1 and 67.2%. Median OS and PFS were 23.6 and 13.4 months, respectively. Toxicities were mild and curable. Conclusion: The combination of gemcitabine and capecitabine is an effective and tolerable treatment for MBC previously treated with anthracyclines and/or taxanes.

With rising life expectancy in cancer patients with bone metastases, the need for local treatment (LT) is expanding. Machine learning (ML) could create reasonable generalizations, the purpose of this article was to evaluate the use of ML model in LT strategies. Patients were treated by an interdisciplinary team in Shanghai Sixth People's Hospital. Visual analog scale (VAS) and Quality of Life (QoL) Questionnaire Bone Metastases Module scores were analyzed before, 1 week, 1, 3, and 6 months after treatments. ML models were used to calculate LT probability, and confusion matrix was used to calculate the accuracy, precision, recall and F1 score of models. ML models were further used to calculate pathological fracture (PF) probability in lung cancer patients. Of 386 patients enrolled between 2016 and 2017, 101 patients underwent LT. Significant improved VAS and pain domains scores were observed in 27 surgery patients at 1, 3 and 6m, while functional domains scores at 3 and 6m. All five scores improved significantly in 46 percutaneous osteoplasty patients at 1w, 1 and 3m. Significant improved VAS and pain domains scores were observed in 28 radiation patients at 1 and 3m, while functional domains scores at 3m. Compared with team decision-making, decision tree was superior to support vector machine and Bayesian neural networks in model building. The VAS scale, primary cancer, Frankel classification, Mirels score, C-terminal telopeptide of type I collagen (CTx), age, mid-fragment of osteocalcin (MID), character of bone metastases, CA153, and visceral metastases were included in the DT model. In 386 patients, the values of decision tree for the accuracy, precision, recall and F1 score were 86.53%, 78.44%, and 64.90% and 0.69 respectively. 124 lung cancer patients were used to calculate PF probability by decision tree. We also put driving gene mutation and five differentially expressed proteins into the model. The VAS scale, character of bone metastases, age, driving gene mutation, C-terminal telopeptide of type I collagen (CTx), mid-fragment of osteocalcin (MID) and enolase 1 (ENO1) were included in the DT model. The sensitivity, specificity and accuracy of DT model was 90.52%, 87.19% and 77.72%. Appropriate LT provided significant pain relief and improvement in QoL. The ML model is effective in helping physicians determine which patient may be the candidate for LT. Citation Format: Hui Zhao, zhiyu wang, jing Sun, yifeng Gu, mengdi Yang, guangyu Yao. Exploiting machine learning in local treatment strategies in cancer patients with bone metastases: A real world clinical trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2059.

Recent genome-wide association studies (GWASs) have identified 15q25.1 as a lung cancer susceptibility locus. Here, we sought to explore the direct carcinogenic effects of genetic variants in this region on the risk of developing lung adenocarcinoma (ADC). Five common SNPs (rs8034191, rs16969968, rs1051730, rs938682, and rs8042374) spanning the 15q25.1 locus were assayed in a case-control study examining a cohort of 301 lung ADCs and 318 healthy controls. Stratification analysis by gender, smoking status, and tumor, node, metastasis (TNM) classification, was performed. In addition, sections from ADC tissue and normal tissue adjacent to tumors were stained with an anti-CHRNA3 (cholinergic receptor nicotinic α3) antibody by immunohistochemistry in 81 cases. Our results demonstrate that rs8042374, a variant of the CHRNA3 gene, is associated with an increased risk of ADC with an OR of 1.76 (95% CI: 1.17–2.65, p = 0.024). This variant was linked to a greater risk of ADC in female nonsmokers (OR (95% CI): 1.81 (1.05–3.12), p = 0.032) and female stage I + II cases (OR (95% CI): 1.92 (1.03–3.57), p = 0.039). Although located within the same gene, rs938682 showed protective effects for smokers, stage III + IV cases, and male stage III + IV cases. Additionally, the CHRNA3 protein level in ADC tissue was slightly higher than in the surrounding normal lung tissue, based on immunohistochemical analysis. Our results suggest that the CHRNA3 polymorphism functions as a genetic modifier of the risk of developing lung ADC in the Chinese population, particularly in nonsmoking females.

We previously identified five miRNAs (miR-1, miR-20a, miR-27a, miR-34a, and miR-423-5p) that are up-regulated in gastric cancer. The goal of this study was to investigate the value of these miRNAs as potential biomarkers for predicting chemosensitivity and prognosis in metastatic or recurrent gastric cancer patients who received first-line chemotherapy. A total of 82 patients with metastatic or recurrent GC receiving first-line chemotherapy were included in our study. The expression levels of the five miRNAs were evaluated using hydrolysis probe-based stem-loop quantitative reverse transcription polymerase chain reaction (qRT-PCR) in individual samples before first-line chemotherapy. Patients receiving first-line chemotherapy with fluoropyrimidine combined with oxaliplatin or paclitaxel were chosen for the chemosensitivity analysis. The relationships between expression of the five-miRNAs and clinicopathological parameters, response to chemotherapy and prognosis were analyzed statistically. Patients with higher miRNA1 expression levels tended to have a higher rate of liver metastasis, and higher miRNA34a expression levels occurred more frequently in males (P = 0.022). The expression of the remaining three miRNAs showed no obvious relationship to any of the clinicopathological features. The partial response rates of the patients with high miRNA1 expression and low miRNA1 expression were 11.1% and 23.1%, respectively (P = 0.048). Similar results were observed for miRNA27a (the partial response rate was 7.7% vs. 25.9%, P = 0.018). Patients with up-regulated miRNA27a expression had a significantly worse overall survival (OS) than patients with lower miRNA27a expression (P = 0.024). In patients with MRGC, miRNA27a is a potential biomarker for predicting resistance to fluoropyrimidine-based chemotherapy and a novel prognostic marker for gastric cancer.

BACKGROUND Genome-wide association studies (GWAS) have identified various genetic susceptibility loci for breast cancer based mainly on European-ancestry populations. Differing linkage disequilibrium patterns exist between European and Asian populations. METHODS Ten SNPs (rs2075555 in COL1A1, rs12652447 in FBXL17, rs10941679 in 5p12/MRPS30, rs11878583 in ZNF577, rs7166081 in SMAD3, rs16917302 in ZNF365, rs311499 in 20q13.3, rs1045485 in CASP8, rs12964873 in CDH1 and rs8170 in 19p13.1) were here genotyped in 1009 Chinese females (487 patients with breast cancer and 522 control subjects) using the Sequenom MassARRAY iPLEX platform. Association analysis based on unconditional logistic regression was carried out to determine the odds ratio (OR) and 95% confidence interval (95% CI) for each SNP. Stratification analyses were carried out based on the estrogen receptor (ER) and progesterone receptor (PR) status. RESULTS Among the 10 SNPs, rs10941679 showed significant association with breast cancer when differences between the case and control groups in this Han Chinese population were compared (30.09% GG, 45.4% GA and 23.7% AA; P = 0.012). Four SNPs (rs311499, rs1045485, rs12964873 and rs8170) showed no polymorphisms in our study. The remaining five SNPs showed no association with breast cancer in the present population. Immunohistochemical tests showed that rs2075555 was associated with ER status; the AA genotype showed greater association with ER negative than ER positive (OR = 0.54, 95% CI, 0.29-0.99; P = 0.046). AA of rs7166081 was also associated with ER status, but showed a greater association with ER positive than negative (OR = 1.59, 95% CI = 1.04-2.44; P = 0.031). However, no significant associations were found among the SNPs and PR status. CONCLUSION In this study using a Han Chinese population, rs10941679 was the only SNP associated with breast cancer risk, indicating a difference between European and Chinese populations in susceptibility loci. Therefore, confirmation studies are necessary before utilization of these loci in Chinese.

e18050 Background: Spinal metastases are very common outcomes within solid malignant tumors, which could lead to various skeletal related events (SREs). The accurate and timely diagnosis is the key to improve prognosis. Recently, artificial intelligence(AI) has assisted doctors in many ways by different AI technologies. In this study, we applicated a deep learning model to classify and locate the metastatic lesions on spinal CT images. Methods: We set up a dataset consisting of 800 patients’ spinal CT images, which contained over 300,000 CT slices. And we built a multi-label classification and vertebrae segmentation model to recognize the metastatic lesions on spinal CT images. Then we trained and tested this model within our dataset, using a data augmentation by random flips and random rotations. Sensitivity and specificity were used to evaluate the performance of the model. Results: Our model showed that the diagnostic utilities of normal lesions were: sensitivity 81.7% and specificity 92%; while the diagnostic utilities of metastatic lesions were: sensitivity 84.7% and specificity 84.5%. Conclusions: Our model can effectively and accurately discriminate spinal metastases on spinal CT images. [Table: see text]

Estrogen receptor-a (ER) protein plays a key role in breast carcinogenesis, and common genetic variants in the corresponding gene locus have been associated with breast cancer risk in different populations. Here, we analyzed estrogen receptor 1 (ESR1) associations in two hospital-based studies of patients from the south of China. Three single-nucleotide polymorphisms (SNPs; rs3757318, rs2046210, and rs3734805) in ESR1 were selected from previous genome-wide association study results and were genotyped using the Sequenom MassARRAY® iPLEX System in 845 breast cancer patients and 882 healthy controls. Association analysis based on unconditional logistic regression was carried out to determine the odds ratio (OR) and 95% confidence interval (95%CI) for each SNP. Stratified analyses according to the status of ER and progesterone receptor (PR) were also performed. Of the three SNPs, rs3757318 did not pass the Hardy-Weinberg equilibrium test and was excluded from the subsequent analysis. The other two SNPs (rs2046210 and rs3734805) were strongly associated with susceptibility to breast cancer. Allele T of rs2046210 and allele C of rs3734805 were risk alleles and the adjusted ORs were 1.348 (95%CI = 1.172-1.550, P = 0.0001) and 1.319 (95%CI = 1.144-1.522, P = 0.0001), respectively. Furthermore, the risk allele of rs2046210 gave negative results for ER and PR expression in an immunohistochemical test, with ORs of 0.602 (95%CI = 0.384-0.944, P = 0.027) and 0.532 (95%CI = 0.338-0.837, P = 0.006), respectively. Our study further supports associations between rs2046210 and rs3734805 and breast cancer risk in Chinese women.

Background: The epidermal growth factor receptor (EGFR) is a potential therapeutic target for breast cancer treatment; however, its use does not lead to a marked clinical response. Studies of non-small cell lung cancer and colorectal cancer showed that mutations of genes in the PIK3CA/AKT and RAS/RAF/MEK pathways, two major signalling cascades downstream of EGFR, might predict resistance to EGFR-targeted agents. Therefore, we examined the frequencies of mutations in these key EGFR pathway genes in Chinese breast cancer patients. Methods: We used a high-throughput mass-spectrometric based cancer gene mutation profiling platform to detect 22 mutations of the PIK3CA, AKT1, BRAF, EGFR, HRAS, and KRAS genes in 120 Chinese women with breast cancer. Results: Thirteen mutations were detected in 12 (10%) of the samples, all of which were invasive ductal carcinomas (two stage I, six stage II, three stage III, and one stage IV). These included one mutation (0.83%) in the EGFR gene (rs121913445-rs121913432), three (2.50%) in the KRAS gene (rs121913530, rs112445441), and nine (7.50%) in the PIK3CA gene (rs121913273, rs104886003, and rs121913279). No mutations were found in the AKT1, BRAF, and HRAS genes. Six (27.27%) of the 22 genotyping assays called mutations in at least one sample and three (50%) of the six assays queried were found to be mutated more than once. Conclusions: Mutations in the EGFR pathway occurred in a small fraction of Chinese breast cancers. However, therapeutics targeting these potential predictive markers should be investigated in depth, especially in Oriental populations.

Exposure to endogenous sex hormones has been reported as a risk factor for breast cancer. The CYP11A1 gene encodes the key enzyme that catalyzes the initial and rate-limiting step in steroid hormone synthesis. In this study, the associations between single nucleotide polymorphisms (SNPs) in CYP11A1 and breast cancer susceptibility were examined. Six SNPs in CYP11A1 were genotyped using the MassARRAY IPLEX platform in 530 breast cancer patients and 546 healthy controls. Association analyses based on a χ(2) test and binary logistic regression were performed to determine the odds ratio (OR) and 95% confidence interval (95% CI) for each SNP. Two loci (rs2959008 and rs2279357) showed evidence of associations with breast cancer risk. The variant genotype C/T-C/C of rs2959008 was significantly associated with a decreased risk (age-adjusted OR, 0.75; 95% CI, 0.58-0.96; P = 0.023) compared with the wild-type TT. However, the homozygous TT variant of rs2279357 exhibited increased susceptibility to breast cancer (age-adjusted OR, 1.44; 95% CI, 1.05-1.98; P = 0.022). The locus rs2959003 also showed an appreciable effect, but no associations were observed for three other SNPs. Our results suggest that polymorphisms of CYP11A1 are related to breast cancer susceptibility in Han Chinese women of South China.

Most of breast cancers are resistant to mammalian target of rapamycin complex 1 (mTORC1) inhibitors rapamycin and rapalogs. Recent studies indicate mTORC2 is emerging as a promising cancer therapeutic target. In this study, we compared the inhibitory effects of targeting mTORC1 with mTORC2 on a variety of breast cancer cell lines and xenograft. We demonstrated that inhibition of mTORC1/2 by mTOR kinase inhibitors PP242 and OSI-027 effectively suppress phosphorylation of Akt (S473) and breast cancer cell proliferation. Targeting of mTORC2 either by kinase inhibitors or rictor knockdown, but not inhibition of mTORC1 either by rapamycin or raptor knockdown promotes serum starvation- or cisplatin-induced apoptosis. Furthermore, targeting of mTORC2 but not mTORC1 efficiently prevent breast cancer cell migration. Most importantly, in vivo administration of PP242 but not rapamycin as single agent effectively prevents breast tumor growth and induces apoptosis in xenograft. Our data suggest that agents that inhibit mTORC2 may have advantages over selective mTORC1 inhibitors in the treatment of breast cancers. Given that mTOR kinase inhibitors are in clinical trials, this study provides a strong rationale for testing the use of mTOR kinase inhibitors or combination of mTOR kinase inhibitors and cisplatin in the clinic.

Introduction: Despite recent advances in targeted and immune-based therapies, the poor prognosis of lung adenocarcinoma (LUAD) with bone metastasis (BM) remains a challenge. Here, we aimed to investigate the potential biomarker for LUAD with BM. Methods: First, we collected 5 patients with traumatic amputation, 5 patients with bone infiltration, 9 LUAD patients who underwent curative resection or thoracoscopic lobectomy and 32 LUAD patients with BM who underwent bone biopsy in the Shanghai Sixth People's Hospital (China) from May 2014 to January 2017. 28 bone biopsy samples and 9 LUAD samples were used for immunohistochemistry assays (IHC) and OS (follow-up period of more than one year). Secondly, RT-PCR, IHC, and Western blotting (WB) were used to assess Aldehyde Dehydrogenase 2 (ALDH2) RNA and protein expression levels in samples of LUAD with BM. The Cancer Genome Atlas (TCGA) and Kaplan Meier plotter (KM Plotter) were used to generate survival curves. Thirdly, we analyzed the methylation associated genes and found DNA Methyltransferase 1 (DNMT1) and methyl-CpG binding domain 4 (MBD4) down-regulated the expression of ALDH2. Fourthly, we explored the impact of ALDH2 on tumor cell function and apoptosis via cell counting kit-8 (CCK8), Transwell and Fluorescence activated cell sorter (FACS). Then, we demonstrated that ALDH2 might affect mitogen-activated protein kinase (MAPK) and Epithelial-mesenchymal transition (EMT) markers through WB assays. Last, to confirm ALDH2 effect in vivo, we injected PLVX-flag-aldh2 and PLVX-flag H1299 cells into the left cardiac ventricle to check the effect of ALDH2 in BM and calculated the overall survival of mice. Results: We identified both mRNA and protein levels of ALDH2 were much lower in tumor tissues than in normal tissues, and they were even lower in tissues that exhibited increased migratory capacity. This low expression feature may be attributed to DNA methylation of ALDH2.The result of over expressing or knocking down ALDH2 showed that this gene inhibited proliferation, migration and promoted apoptosis both in vivo and in vitro. Overexpression of ALDH2 can inhibit MAPK signaling pathway and EMT in H1299. It also inhibited the occurrence of BM in LUAD and expanded survival in mice (p=0.003). Conclusions: This is the first time that instance where ALDH2 was associated with disease severity and progression in LUAD patients with BM. Thus, with this study, we have identified potential biomarkers and therapeutic targets for this disease. Supported by the National Natural Science Foundation of China (grant No. 81672852,81602519), a three year action plan to promote clinical skills and clinical innovation in municipal hospitals (20164Y0099), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20172024). Citation Format: Mengdi Yang, Guangyu Yao, Zhiyu Wang, Jing Sun, Yiyi Zhou, Yifeng Gu, Hui Zhao. The differential expression of ALDH2 is correlated with prognosis of lungadenocarcinoma with bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-319.

e13028Background: Bone marrow metastasis from breast cancer (BC) is relatively rare, and the prognosis is poor. This study was to investigate breast cancer patients with bone or bone marrow metasta...

Background Young breast cancer occupies a higher and higher proportion of breast cancer, especially in Asia, and is associated with a more unfavorable prognosis compared with the disease arising in older women. However, the poor prognosis of young breast cancer cannot be fully explained by the clinical and molecular factors. Methods This study investigated 1125 Chinese breast cancer patients diagnosed from 2009 to 2013. A data mining of gene expression profiles was performed for the young and older breast cancer patients, identifying significantly differentially expressed genes. Quantitative RT-PCR, Western blotting and immunohistochemistry assay were carried out for the clinical sample validations. Results The investigation firstly displayed that young patients (≤45 years) accounted for 47.6 % (535/1125) of breast cancer, and clinically associated with some unfavorable factors related to poor prognosis, such as invasive pathological type, high tumor grade, lymph node positive, ER negative and triple-negative subtype. Subsequently, 553 significantly differentially expressed genes were identified by the data mining. Of them, a set of genes related to immune function were observed to be up-regulated in young patients with breast cancer. Impressively, the CXCL13 (C-X-C motif chemokine 13) expression level showed the most significant difference (FC = 2.64, P = 8.2 × 10−4). Furthermore, the validations with clinical samples and correlation analysis demonstrated that CXCL13 was indeed highly expressed in young breast cancer and closely associated with some prognostic factors including lymph node positive and ER negative. Conclusion This is the first to indicate the clinical relevance of CXCL13 to young breast cancer and represents a potential therapeutic target for young breast cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0521-1) contains supplementary material, which is available to authorized users.

Purpose Results from previous randomised controlled trials (RCTs) investigating whether the addition of bevacizumab to neoadjuvant chemotherapy (NAC) could statistically significantly increase the pathological complete response (pCR) and to identify which subgroup would benefit most from such regimens have produced conflicting results. This meta-analysis was designed to assess the efficacy and safety of bevacizumab plus chemotherapy compared with chemotherapy alone in the neoadjuvant setting. Methods A literature search of MEDLINE, EMBASE, Web of Science, and the Cochrane library was performed to identify eligible studies. The primary endpoint of interest was pCR. The secondary endpoints were clinical complete rate (cCR), surgery rate, breast-conserving surgery (BCS) rate, and toxicity. The meta-analysis was performed using Review Manager software version 5.3. Results Nine RCTs matched the selection criteria, yielding a total of 4967 patients (bevacizumab plus chemotherapy: 50.1%, chemotherapy alone: 49.9%). The results of this meta-analysis demonstrated that the addition of bevacizumab to NAC significantly increased the pCR rate (odds ratio [OR] = 1.34 [1.18–1.54]; P < 0.0001) compared with chemotherapy alone. Subgroup analysis showed that the effect of bevacizumab was more pronounced in patients with HER2-negative cancer (OR = 1.34 [1.17–1.54]; P < 0.0001) compared with HER2-positive cancer (OR = 1.69 [0.90–3.20]; P = 0.11). Similarly, in patients with HER2-negative cancer, the effect of bevacizumab was also more pronounced in patients with HR-negative cancer (OR = 1.38 [1.09–1.74]; P = 0.007) compared with HR-positive cancer (OR = 1.36 [0.78–2.35]; P = 0.27). No significant differences were observed between the groups with respect to cCR, surgery rate, or BCS rate. Additionally bevacizumab was associated with a higher incidence of neutropenia, febrile neutropenia, and hand–foot syndrome. Conclusions Higher proportions of patients achieved pCR when bevacizumab was added to NAC compared with when they received chemotherapy alone; acceptable toxicities were also found. Subgroup analysis demonstrated that patients with histologically confirmed HER2-negative and HR-negative breast cancer benefited the most.

The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612); Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 ((95% confidence intervals (CI), 1.10–1.57)) and 1.26 (95% CI, 1.02–1.56), respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer.

Background Recent evidence suggests that vascular endothelial growth factor-C (VEGF-C)- dependent tumour production promotes lymphangiogenesis, while membrane-type matrix 1 metalloproteinase (MT1-MMP) is involved in the critical steps leading to carcinogenesis. However, the role of MT1-MMP in lymphangiogenesis and lymphatic metastasis remains poorly understood. In the present study, we investigated the relationship between MT1-MMP and VEGF-C in human breast cancer and correlated MT1-MMP and VEGF-C expression with lymphangiogenesis and prognosis. Methods MT1-MMP and VEGF-C levels were compared in five breast carcinoma cell lines. We used a membrane invasion assay to assess the effect of MT1-MMP and VEGF-C expression, as well as anti-MT1-MMP and VEGF-C antibodies, on cancer cell invasion. We further assessed MT1-MMP and VEGF-C immunoreactivity and lymph vessels in a cohort of human breast cancer specimens (n = 106) and associated MT1-MMP and VEGF-C expression with clinicopathological parameters, such as lymphatic vessel density (LVD), and patient prognosis. Results MT1-MMP and VEGF-C expression differed among the five breast cancer cell lines and MT1-MMP and VEGF-C expression were correlated with tumour cell invasion. VEGF-C mRNA expression levels and invasive activity of MDA-MB-231 cells was inhibited by an anti-MT1-MMP antibody in a concentration-dependent manner. A significant correlation was found between the expression of MT1-MMP and VEGF-C in breast cancer patient samples and elevated MT1-MMP and VEGF-C expression was associated with higher LVD, lymph node metastasis, cancer stage, and a decline in overall survival rates. Conclusions Our data demonstrate that MT1-MMP expression is closely correlated with VEGF-C expression, and that MT1-MMP promotes lymphangiogenesis by up-regulating VEGF-C expression in human breast cancer. Thus, elevated MT1-MMP may serve as a significant prognostic factor in breast cancer.

Patterns of DNA methylation are established and maintained by a family of DNA methyltransferases (DNMTs). Aberrant promoter DNA methylation of tumor suppressor genes is found in breast cancer. Association studies between DNMT gene polymorphisms and breast cancer in various populations have reported inconsistent results. This study assessed the associations of single nucleotide polymorphisms (SNPs) in DNMT1, DNMT3A, DNMT3B, DNMT3L, and DNMT2 with breast cancer among Han Chinese women from South China. Sixteen SNPs (rs2114724, rs2228611, rs2228612, rs8101866, and rs16999593 in DNMT1; rs13420827, rs11887120, rs13428812, rs1550117, rs11695471, and rs6733301 in DNMT3A; rs2424908, rs2424913, and rs6087990 in DNMT3B; rs113593938 in DNMT3L, and rs11254413 in DNMT2) in 408 women with breast cancer and 469 controls were genotyped using a MassARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. Two SNPs, rs16999593 in DNMT1 and rs2424908 in DNMT3B, were significantly associated with breast cancer risk. The heterozygous genotype CT of rs16999593 was associated with increased breast cancer risk [odds ratio (OR) = 1.60; 95% confidence interval (95%CI) = 1.20-2.14; P = 0.0052], whereas rs2424908 was associated with decreased risk (OR = 0.62; 95%CI = 0.46-0.84; P = 0.0061). Other DNMT polymorphisms showed no significant associations with breast cancer risk in the study population. Haplotype CGTC of rs2114724, rs2228611, rs8101866, and rs16999593 in DNMT1 differed significantly as a risk factor between the case and control groups (OR = 1.51; 95%CI = 1.18-1.93; P = 0.0012). The heterozygous genotypes of rs16999593 in DNMT1 and rs2424908 in DNMT3B were strongly associated with breast cancer risk.

Nordihydroguaiaretic acid (NDGA) is a natural phenolic compound isolated from the creosote bush Larrea divaricata, which has anti-tumor activities both in vitro and in vivo. Its analogs are in clinical development for use in refractory solid tumors. But the mechanisms underlying the anti-cancer effect of NDGA are not fully understood. In this study, we identified mammalian target of rapamycin complex 1 (mTORC1) as a target of NDGA both in cultured breast cancer cells and in xenograft models. NDGA effectively inhibited basal level of mTORC1 but not mTORC2 activity in breast cancer cell lines. NDGA also suppressed mTORC1 downstream signaling such as expression of cyclin D1, hypoxia-inducible factor-α and VEGF, and prevented proliferation in breast cancer cells. Although NDGA stimulated AMP-activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and TSC2 deletion could not diminish the inhibition of mTORC1 by NDGA. Subsequent studies revealed that NDGA may also direct target mTORC1 complex because NDGA suppressed amino acids- and insulin-stimulated mTORC1 and acted like rapamycin to disrupt mTOR–Raptor interaction. Most importantly, NDGA repressed breast tumor growth and targeted mTORC1 and its downstream signaling in xenograft models. Together our data provide a novel mechanism for NDGA activity which could help explain its anti-cancer activity. Disruption of mTOR–Raptor complex and activation of AMPK/TSC signaling may contribute to inhibitory effects of NDGA against mTORC1. Our data also raise the possibility that NDGA, as an mTORC1 inhibitor, may have a broad spectrum of action on breast cancers.

Background It is controversial for prognosis of invasive micropapillary carcinoma (IMPC) compared with invasive ductal carcinoma (IDC) of the breast. To better understand the difference between IMPC and IDC prognoses, we conducted this retrospective study. Methods Data from 33 patients with IMPC were retrospectively reviewed, and the clinicopathologic characteristics and survival status were compared with those of 347 patients with IDC who were treated during the same period. Results The IMPC cases were of larger tumor size, greater proportion of nodal involvement, and an increased incidence of lymphovascular invasion compared with IDC cases. The overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and failure-free survival (FFS) rates were not significantly different between IMPC and IDC. The 3-year OS rate was 97 vs 94.2 % for the IMPC and IDC patients, respectively. The 3-year FFS rate was 87.9 vs 86.2 % for the IMPC and IDC patients, respectively. For IMPC patients, the 3-year LRFS rate was 93.9 % and in IDC patients was 89.0 %. The 3-year DMFS rates of IMPC patients was 90.9 % and IDC patients was 89 %. Conclusions IMPC had poor clinical characteristics, but it showed no difference in OS, FFS, LRFS, and DMFS compare with IDC.