AI models predicting breast cancer distant metastasis using LightGBM with clinical blood markers and ultrasound maximum diameter.

Breast cancer metastasis significantly impacts women's health globally. This study aimed to construct predictive models using clinical blood markers and ultrasound data to predict distant metastasis in breast cancer patients, ensuring clinical applicability, cost-effectiveness, relative non-invasiveness, and accessibility of these models. Analysis was conducted on data from 416 patients across two centers, focusing on clinical blood markers (tumor markers, liver and kidney function indicators, blood lipid markers, cardiovascular biomarkers) and maximum lesion diameter from ultrasound. Feature reduction was performed using Spearman correlation and LASSO regression. Two models were built using LightGBM: a clinical model (using clinical blood markers) and a combined model (incorporating clinical blood markers and ultrasound features), validated in training, internal test, and external validation (test1) cohorts. Feature importance analysis was conducted for both models, followed by univariate and multivariate regression analyses of these features. The AUC values of the clinical model in the training, internal test, and external validation (test1) cohorts were 0.950, 0.795, and 0.883, respectively. The combined model showed AUC values of 0.955, 0.835, and 0.918 in the training, internal test, and external validation (test1) cohorts, respectively. Clinical utility curve analysis indicated the combined model's superior net benefit in identifying breast cancer with distant metastasis across all cohorts. This suggests the combined model's superior discriminatory ability and strong generalization performance. Creatine kinase isoenzyme (CK-MB), CEA, CA153, albumin, creatine kinase, and maximum lesion diameter from ultrasound played significant roles in model prediction. CA153, CK-MB, lipoprotein (a), and maximum lesion diameter from ultrasound positively correlated with breast cancer distant metastasis, while indirect bilirubin and magnesium ions showed negative correlations. This study successfully utilized clinical blood markers and ultrasound data to develop AI models for predicting distant metastasis in breast cancer. The combined model, incorporating clinical blood markers and ultrasound features, exhibited higher accuracy, suggesting its potential clinical utility in predicting and identifying breast cancer distant metastasis. These findings highlight the potential prospects of developing cost-effective and accessible predictive tools in clinical oncology.

Development and validation of AI models using LR and LightGBM for predicting distant metastasis in breast cancer: a dual-center study.

Objective: This study aims to develop an artificial intelligence model utilizing clinical blood markers, ultrasound data, and breast biopsy pathological information to predict the distant metastasis in breast cancer patients. Methods: Data from two medical centers were utilized, Clinical blood markers, ultrasound data, and breast biopsy pathological information were separately extracted and selected. Feature dimensionality reduction was performed using Spearman correlation and LASSO regression. Predictive models were constructed using LR and LightGBM machine learning algorithms and validated on internal and external validation sets. Feature correlation analysis was conducted for both models. Results: The LR model achieved AUC values of 0.892, 0.816, and 0.817 for the training, internal validation, and external validation cohorts, respectively. The LightGBM model achieved AUC values of 0.971, 0.861, and 0.890 for the same cohorts, respectively. Clinical decision curve analysis showed a superior net benefit of the LightGBM model over the LR model in predicting distant metastasis in breast cancer. Key features identified included creatine kinase isoenzyme (CK-MB) and alpha-hydroxybutyrate dehydrogenase. Conclusion: This study developed an artificial intelligence model using clinical blood markers, ultrasound data, and pathological information to identify distant metastasis in breast cancer patients. The LightGBM model demonstrated superior predictive accuracy and clinical applicability, suggesting it as a promising tool for early diagnosis of distant metastasis in breast cancer.

Effect of mastectomy on gut microbiota and its metabolites in patients with breast cancer.

Background: The relationship between gut microbiota and breast cancer has been extensively studied; however, changes in gut microbiota after breast cancer surgery are still largely unknown. Materials and methods: A total of 20 patients with breast cancer underwent routine open surgery at the First Affiliated Hospital of Hainan Medical College from 1 June 2022 to 1 December 2022. Stool samples were collected from the patients undergoing mastectomy for breast cancer preoperatively, 3 days later, and 7 days later postoperatively. The stool samples were subjected to 16s rRNA sequencing. Results: Surgery did not affect the α-diversity of gut microbiota. The ß-diversity and composition of gut microorganisms were significantly affected by surgery in breast cancer patients. Both linear discriminant analysis effect size (LEfSe) analysis and between-group differences analysis showed that surgery led to a decrease in the abundance of Firmicutes and Lachnospiraceae and an increase in the abundance of Proteobacteria and Enterobacteriaceae. Moreover, 127 differential metabolites were screened and classified into 5 categories based on their changing trends. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed significant changes in the phenylalanine metabolic pathway and exogenous substance metabolic pathway. Eight characterized metabolites were screened using ROC analysis. Conclusion: Our study found that breast cancer surgery significantly altered gut microbiota composition and metabolites, with a decrease in beneficial bacteria and an increase in potentially harmful bacteria. This underscores the importance of enhanced postoperative management to optimize gut microbiota.

A Novel Endoscopic Approach for Treating Breast Cancer: Haigui-1 Hole.

OBJECTIVE: Endoscopic surgery is an effective technique for preserving the nipple and areola, as well as for sentinel lymph node biopsy and breast implant reconstruction. However, the technical challenges associated with endoscopic surgery have limited its widespread adoption. METHODS: In the normal single-port endoscopic surgery, the ultrasonic knife was accessed through the retractor. In our modified procedure, a tiny 5 mm incision was made at the lateral margin underneath the breast, serving as the second entry port for the ultrasonic scalpel, which was referred to as the "Haigui-1 hole". Preoperative and postoperative indicators such as blood loss, operative time, and postoperative drainage volume were collected. Differences between parameters were compared using Student's t test. RESULTS: Endoscopic surgery with the assistance of the "Haigui-1 hole" led to preserved breast aesthetics with minimal scarring. Moreover, "Haigui-1 hole" surgery significantly reduced the operation time, intraoperative bleeding, and postoperative drainage volume compared to normal single-port endoscopic surgery. CONCLUSION: The "Haigui-1 hole" procedure, which involves the addition of a second entrance to improve the maneuverability of the ultrasonic knife, is worthy of further promotion.

Identifying the Preoperative Radiological Risk Features in Patients with Leptomeningeal Carcinomatosis Undergoing Cerebrospinal Fluid Drainage.

BACKGROUND: Patients with leptomeningeal carcinomatosis (LMC) experience a poor prognosis and rapid progression, and cerebrospinal fluid drainage (CSFD) is used to manage intracranial hypertension and hydrocephalus in LMC patients. This study aims to describe a novel discovery of preoperative radiological features in patients who underwent CSFD for LMC. METHODS: A retrospective review was conducted during the past 5 years of LMC patients with intracranial hypertension and hydrocephalus who underwent CSFD. We evaluated the patients' preoperative radiological features, clinical characteristics, and survival times. RESULTS: A total of 36 patients were included. Of the 36 patients, 34 underwent ventriculoperitoneal shunting, and 2 patients underwent only external ventricular drainage due to rapid progression. The median preoperative Karnofsky performance scale score was 40.0 (interquartile range [IQR], 20.0-40.0). The median survival time after surgery was 5 months (IQR, 0.00-10.43 months). Of the 36 patients, 24 (66.7%) had supratentorial cerebral edema before surgery, including 14 patients (38.9%) with features of disproportionately enlarged subarachnoid space hydrocephalus (DESH). Four patients (11.1%) exhibited cerebellar swelling and had a median survival time of 0.27 month (IQR, 0.00-0.56 month). Nine patients (25%) have enhancement lesions on the cerebellum. The survival curve analysis shows that patients with features of cerebellar enhancement have shorter survival times than other patients. Patients with DESH features have longer survival times compared with those with global cerebral edema. CONCLUSIONS: Patients with radiological features of cerebellar enhancement have shorter postoperative survival than other patients; however, those with supratentorial cerebral edema, especially features of DESH, could benefit from CSFD. Patients with cerebellar swelling should avoid undergoing CSFD.

IKKα inhibition re-sensitizes acquired adriamycin-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis.

IKKα has been shown to be responsible of multiple pro-tumorigenic functions and therapy resistance independent of canonical NF-κB, but its role in acquired chemotherapy resistance in breast cancer remains unclarified. In this study, we obtained pre-treatment biopsy and post-treatment mastectomy specimens from a retrospective cohort of triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy(NAC) (n = 43). Immunohistochemical methods were used to detect the expression of IKKα before and after NAC, and the relationship between IKKα and the pathologic response to NAC was examined. In addition, we developed a new ADR-resistant MDA-MB-231 cell line(MDA-MB-231/ADR) and analyzed these cells for changes in IKKα expression, the role and mechanisms of the increased IKKα in promoting drug resistance were determined in vitro and in vivo. We demonstrated that the expression of IKKα in residual TNBC tissues after chemotherapy was significantly higher than that before chemotherapy, and was positively correlated with lower pathological reaction. IKKα expression was significantly higher in ADR-resistant TNBC cells than in ADR-sensitive cells, IKKα knockdown results in apoptotic cell death of chemoresistant cells upon drug treatment. Moreover, IKKα knockdown promotes chemotherapeutic drug-induced tumor cell death in an transplanted tumor mouse model. Functionally, we demonstrated that IKKα knockdown significantly upregulated the expression of cleaved caspase 3 and Bax and inhibited the expression of Bcl-2 upon ADR treatment. Our findings highlighted that IKKα exerts an important and previously unknown role in promoting chemoresistance in TNBC, combining IKKα inhibition with chemotherapy may be an effective strategy to improve treatment outcome in chemoresistant TNBC patients.

Identification of the prognostic value of Th1/Th2 ratio and a novel prognostic signature in basal-like breast cancer.

BACKGROUND: Breast cancer is a heterogeneous group of diseases. The polarization of CD4+ T helper (Th) lymphocytes (mainly Th1 and Th2) may differ in breast cancers with different outcomes, but this has not been fully validated. METHODS: This study is a bioinformatic analysis, in which differentially expressed genes (DEGs) were identified in patients with low and high Th1/Th2 ratios. And then, DEG functions, hub genes and independent predictors were determined. RESULTS: Low Th1/Th2 ratio was associated with poor outcome in Luminal A and basal-like breast cancer (p < 0.05). GSEA and KEGG analysis of DEGs obtained from comparing low and high Th1/Th2 ratios illuminated downregulation of immune-related gene sets and pathways affecting Th1/Th2 balance toward Th2 polarization (p < 0.05). Survival and Cox analyses of all the DEGs confirmed CCL1 and MYH6 were independent protective factors and IFNK and SOAT2 were independent risk factors for basal-like breast cancer (95%CI: 1.06-2.5, p = 0.026). Then a four-gene signature was constructed and achieved a promising prognostic value (C-index = 0.82; AUC = 0.826). CONCLUSIONS: Low Th1/Th2 ratio predicts poor outcome in Luminal A and Basal-like breast cancer, and downregulation of immune-related gene sets and pathways contribute to Th1/Th2 balance toward Th2 polarization. CCL1, MYH6, IFNK, and SOAT2 have an independent prognostic value of survival outcome and might be novel markers in basal-like breast cancer.

Synergistic anticancer mechanisms of curcumol and paclitaxel in triple-negative breast cancer treatment may involve down-regulating ZBTB7A expression via the NF-B signaling pathway.

Objectives: This study aimed to verify whether curcumol combined with paclitaxel exerted synergistic antiproliferative and proapoptotic effects in MDA-MB-231 mammary cancer cells. Materials and Methods: The effects of different concentrations of CC, PTX, and their combination on the proliferation of MDA-MB-231 mammary cancer cells were determined by CCK-8 laboratory tests. Combination index (CI) was calculated using CompuSyn software. Colony formation assays, Hoechst 33258 immunofluorescence staining, and flow cytometry were carried out to observe proliferation and apoptosis in each group. The protein expression of PCNA, Bcl-2, Bax, ZBTB7A, p-p65, and NF-ƙB p65 was detected by western blotting. The xenograft tumor volume and body mass of nude mice were measured. Immunohistochemistry was used to detect the expression of PCNA , NF-B p65 and ZBTB7A. TUNEL and DAPI staining were used to detect the apoptosis of tumor cells. Results: Curcumol combined with paclitaxel exerted a significant inhibitory effect on proliferation of MDA-MB-231 cells in the CCK-8 laboratory test. Hoechst 33258 immunofluorescence staining, flow cytometry, TUNEL, and DAPI apoptosis staining demonstrated that cell apoptosis was the highest in the CC+PTX group in vivo and in vitro. Expression of PCNA, Bcl-2, ZBTB7A, p-p65, and NF-B p65 was lowest in the CC+PTX group, while the expression of Bax was highest. The growth of xenograft tumors in the CC+PTX group was most notably suppressed. Immunohistochemistry showed that expression of PCNA, ZBTB7A, and NF-ƙB p65 was the lowest in the CC+PTX group. Conclusion: Curcumol combined with paclitaxel exerted a synergistic antiproliferative and proapoptotic effect on triple-negative breast cancer cells.

Long non-coding RNA (LncRNA) CHROMR promotes the expression of the CNNM1 gene by adsorbing hsa-miR-1299 to obtain drug resistance in diffuse large B lymphoma cells.

Background: Long non-coding RNA (LncRNA) play roles in different diseases, LncRNA is differentially expressed in diffuse large B cell lines with varying degrees of resistance to rituximab. Methods: In the GEO database (GSE159852), we found that CHROMR (cholesterol induced regulator of metabolism RNA) may be differentially expressed in different rituximab-resistant diffuse large B lymphoma cell lines. We also verified the expression level in cell lines and verified the role of CHROMR in acquiring cell drug resistance through various biological function experiments. We predict that there may be a potential regulatory mechanism for CHROMR and validated it. Results: We found that CHROMR was differentially expressed in different rituximab-resistant cell lines. When the rituximab-sensitive cell line SU_DHL_4 was stimulated by rituximab, flow experiments demonstrated that overexpression of CHROMR could reduce the level of cell apoptosis and the proportion of arrested cells in the G2/M phase of the cell cycle. cck8 experiments demonstrated that overexpression of CHROMR increased cell proliferation. Western Blot (WB) experiments confirmed that overexpression of CHROMR reduced the expression of apoptosis-related proteins. Dual-luciferase and recovery experiments suggested that CHROMR acted through the CHROMR/hsa-miR-1299/CNNM1 pathway. Conclusions: lncRNA CHROMR promotes the expression of the CNNM1 gene by adsorbing hsa-miR-1299 to obtain drug resistance in diffuse large B lymphoma cells.

Predictive and prognostic effect of HO-1 expression in breast cancer patients undergoing neoadjuvant chemotherapy.

PURPOSE: Heme oxygenase-1 (HO-1) has complex biological function, and is a candidate oncogene with a wide variety of deleterious functions in breast cancer. Here, we evaluated the relationship between expression of HO-1 protein with clinical response to neoadjuvant chemotherapy (NAC) in breast cancer patients. METHODS: We used immunohistochemistry (IHC) to determine expression of HO-1 protein from core needle biopsy before NAC, then applied univariate and multivariate analyses to understand the relationship between HO-1 with pathological complete response (pCR) outcomes. Next, Kaplan-Meier and Log-rank tests were used to compare disease-free survival (DFS) and overall survival (OS), between groups, and Cox proportional hazards regression analysis applied for prognostic evaluation. RESULTS: A total of 575 patients with locally advanced invasive breast cancer were included in the study, of which 111 (19.3%) achieved pCR after NAC. Results from multivariate analysis showed that high HO-1 expression was an independent predictor of low pCR rate (OR 0.254, 95% CI 0.026-0.643, p = 0.002). Moreover, results from survival analysis showed that high HO-1 expression was significantly associated with shorter DFS (HR 4.843, 95% CI 1.205-32.572, p = 0.026), but not with OS (HR 3.219, 95% CI 0.928-32.124, p = 0.071). Furthermore, HO-1 expression was significantly associated with lower pCR rate (OR 0.102, 95% CI 0.013-0.352), p = 0.001), poor DFS (HR 8.562, 95% CI 1.592-34.950, p = 0.009), and OS (HR 7.835, 95% CI 1.220-56.213, p = 0.023) of patients with triple-negative breast cancer (TNBC) patients. CONCLUSION: Our results indicated that HO-1 expression is not only a biomarker for predicting pCR, but also a prognostic factor in breast cancer patients in a neoadjuvant setting, especially in TNBC subgroups.

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression.

Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, in which POLD1 may serve as a potential target. However, the anticancer mechanism of RSV on triple negative breast cancer (TNBC) remains unclear. In the present study, the antitumor effects and mechanism of RSV on TNBC cells were analyzed by RNA sequencing (RNA-seq), which was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, and hematoxylin-eosin (HE) staining. According to the corresponding findings, the survival rate of MDA-MB-231 cells gradually decreased as RSV treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected by RSV treatment were mainly involved in apoptosis and the p53 signaling pathway. Moreover, apoptosis of MDA-MB-231 cells induced by RSV was observed to be mainly mediated by POLD1. When treated with RSV, the expression levels of full length PARP1, PCNA, and BCL-2 were found to be significantly reduced, and the expression level of Cleaved-PARP1 as well as Cleaved-Caspase3 increased significantly. Additionally, the mRNA expression of POLD1 was significantly reduced after treatment with RSV, and the protein expression level was also inhibited by RSV in a concentration-dependent manner. The prediction of domain interaction suggested that RSV may bind to at least five functional domains of the POLD1 protein (6s1m, 6s1n, 6s1o, 6tny and 6tnz). Furthermore, after RSV treatment, the anti-apoptotic index (PCNA, BCL-2) of MDA-MB-231 cells was found to decrease while the apoptosis index (caspase3) increased. Moreover, the overexpression of POLD1 reduced the extent of apoptosis observed in MDA-MB-231 cells following RSV treatment. Moreover, animal experimental results showed that RSV had a significant inhibitory effect on the growth of live tumors, while POLD1 overexpression was shown to antagonize this inhibitory effect. Accordingly, this study's findings reveal that RSV may promote the apoptosis of TNBC cells by reducing the expression of POLD1 to activate the apoptotic pathway, which may serve as a potential therapy for the treatment of TNBC.

Advanced-platelet-rich fibrin extract promotes adipogenic and osteogenic differentiation of human adipose-derived stem cells in a dose-dependent manner in vitro.

Advanced platelet-rich fibrin (A-PRF) is an autogenous biological material obtained from peripheral blood. A-PRF extract (A-PRFe) contains a high concentration of various cytokines that are increasingly appreciated for their roles in improving stem cell repairing function during tissue regeneration. However, the optimal A-PRFe concentration to stimulate stem cells is unknown. This study aimed to identify the optimal concentrations of A-PRFe to promote adipogenic and osteogenic differentiation of human adipose-derived stem cells (ASCs). We produced A-PRFe from A-PRF clots by centrifuging fresh peripheral blood samples and isolated and identified ASCs using surface CD markers and multilineage differentiation potential. Enzyme-linked immunosorbent assay (ELISA) showed the concentrations of several cytokines, including b-FGF, PDGF-BB, and others, increased gradually, peaked on day 7 and then decreased. Cell proliferation assays showed A-PRFe significantly stimulated ASC proliferation, and proliferation significantly increased at higher A-PRFe doses. The degree of adipogenic and osteogenic differentiation increased at higher A-PRFe concentrations in the culture medium, as determined by oil red O and alizarin red staining. Reverse transcription polymerase chain reaction (RT-PCR) showed that expression levels of genes related to adipogenic/osteogenic differentiation (PPARγ2, C/EBPα, FABP4, Adiponectin, and ALP, OPN, OCN, RUNX2), paracrine (HIF-1α, VEGF, IGF-2) and immunoregulation (HSP70, IL-8) function were higher in groups with a higher concentration of A-PRFe than in lower concentration groups. This study demonstrates that A-PRFe is ideal for use in ASC applications in regenerative medicine because it improves biological functions, including proliferation, adipogenic/osteogenic differentiation, and paracrine function in a dose-dependent manner.

Capsaicin Inhibits Proliferation and Induces Apoptosis in Breast Cancer by Down-Regulating FBI-1-Mediated NF-κB Pathway.

BACKGROUND: As a natural compound extracted from a variety of hot peppers, capsaicin has drawn increasing attention to its anti-cancer effects against multiple human cancers including breast cancer. FBI-1 is a major proto-oncogene negatively regulating the transcription of many tumor suppressor genes, and plays a vital role in tumorigenesis and progression. However, whether FBI-1 is involved in capsaicin-induced breast cancer suppression has yet to be ascertained. This study aimed to investigate the effects of capsaicin on proliferation and apoptosis and its association with FBI-1 expression in breast cancer. METHODS: CCK-8 and morphological observation assay were employed to detect cell proliferation. Flow cytometry and TUNEL assay were conducted to detect cell apoptosis. RNA interference technique was used to overexpress or silence FBI-1 expression. qRT-PCR and/or Western blot analysis were applied to detect the protein expression of FBI-1, Ki-67, Bcl-2, Bax, cleaved-Caspase 3, Survivin and NF-κB p65. Xenograft model in nude mice was established to assess the in vivo effects. RESULTS: Capsaicin significantly inhibited proliferation and induced apoptosis in breast cancer in vitro and in vivo, along with decreased FBI-1, Ki-67, Bcl-2 and Survivin protein expression, increased Bax protein expression and activated Caspase 3. Furthermore, FBI-1 overexpression obviously attenuated the capsaicin-induced anti-proliferation and pro-apoptosis effect, accompanied with the above-mentioned proteins reversed, whereas FBI-1 silencing generated exactly the opposite response. In addition, as a target gene of FBI-1, NF-κB was inactivated by p65 nuclear translocation suppressed with capsaicin treatment, which was perceptibly weakened with FBI-1 overexpression or enhanced with FBI-1 silencing. CONCLUSION: This study reveals that FBI-1 is closely involved in capsaicin-induced anti-proliferation and pro-apoptosis of breast cancer. The underlying mechanism may be related to down-regulation of FBI-1-mediated NF-κB pathway. Targeting FBI-1 with capsaicin may be a promising therapeutic strategy in patients with breast cancer.

Impact of Primary Site Surgery on Survival of Patients with de novo Stage IV Breast Cancer.

PURPOSE: The efficacy of primary site surgery in patients with de novo stage IV breast cancer remains controversial. However, few real-world studies have evaluated the benefits of local surgery on the primary site of stage IV breast cancer in China. The purpose of this study was to investigate the role of local surgery in the de novo stage IV breast cancer. MATERIALS AND METHODS: Women with metastatic breast cancer at diagnosis were identified from Guangxi medical university cancer hospital (China) database from 2009 to 2017. The clinical and tumor features, surgical treatment, and survival rates were compared between surgical and non-surgical patients. RESULTS: Two hundred forty-three patients were included, of whom 125 underwent primary site surgery. Patients who underwent surgery were more often had small primary tumors, fewer lymph node metastases, and had less visceral involvement. Patients in the surgery group had dramatically longer OS (median 35 vs 22 months, log-rank P=0.006). Stratified survival analysis showed that patients with bone metastasis alone or ≤3 metastasis benefit from surgery, while patients with visceral metastasis did not benefit from surgery. In multivariate analysis, surgical treatment, estrogen receptor status, progesterone receptor status and visceral metastases remained independent factors for survival. CONCLUSION: Surgical resection of the primary site can improve survival in selected de novo stage IV breast cancer patients.

Aberrant ALOX5 Activation Correlates with HER2 Status and Mediates Breast Cancer Biological Activities through Multiple Mechanisms.

Arachidonate lipoxygenases (ALOX) have been implicated in playing a critical role in tumorigenesis, development, and metastasis. We previously reported that ALOX12 is involved in breast cancer chemoresistance. In this study, we demonstrate that the ALOX5 activation correlates with the HER2 expression and mediates breast cancer growth and migration. We found that the ALOX5 expression and activity were upregulated in breast cancer patients, particularly in those tissues with HER2-positive. ALOX5 upregulation was also observed in HER2-positive breast cancer cells. In contrast, HER2 inhibition led to decreased expression and activity of ALOX5 but not ALOX5AP, suggesting that HER2 specifically regulates the ALOX5 expression and activity in breast cancer cells. We further demonstrated that ALOX5 is important for breast cancer biological activities with the predominant roles in growth and migration, likely through RhoA, focal adhesion, and PI3K/Akt/mTOR signaling but not epithelial mesenchymal transition (EMT). Our work is the first to report a correlation between the ALOX5 activity and HER2 overexpression in breast cancer. Our findings also highlight the therapeutic value of inhibiting ALOX5 in breast cancer, particularly those patients with the HER2 overexpression.

Sodium Butyrate Combined with Docetaxel for the Treatment of Lung Adenocarcinoma A549 Cells by Targeting Gli1.

PURPOSE: This study is aimed to investigate the combined treating efficacy of sodium butyrate and docetaxel on proliferation and apoptosis of the lung adenocarcinoma A549 cell line based on Gli1 regulation in vitro and in vivo. MATERIALS AND METHODS: RNA interference method was used to overexpress Gli1 in A549 cells. Cells were treated with varying concentrations of sodium butyrate, docetaxel or both in combination. CCK-8, colony formation assay, Hoechst 33258 staining, flow cytometry and TUNEL assay were employed to detect proliferation, cell cycle and apoptosis. qRT-PCR and Western blot analysis were applied to detect the mRNA and protein expression of Gli1. In vivo tumorigenicity was detected by tumor transplantation in nude mice. Downstream protein levels of Gli1 were detected using Western blot assay. RESULTS: It was found that sodium butyrate or docetaxel alone, respectively, inhibited proliferation and promoted apoptosis of A549 cells in vitro and in vivo, while the combination of the two generated significantly higher responses, which were also effective in another lung adenocarcinoma cell line H1299. Furthermore, the combined therapy had an additive effect in suppressing Gli1 expression and regulating the expression of its downstream proteins that involve in proliferation, cell cycle and apoptosis of A549 cells in vitro and in vivo, including decreased protein expression of Ki-67, CDK1, CDK2, Cyclin D1, Bcl-2 and Survivin, and increased protein expression of Cyclin A, p21, Bax and cleaved-Caspase 3. On the other hand, Gli1 overexpression perceptibly reversed the above-mentioned additive effect in vitro and in vivo. CONCLUSION: This study demonstrates that the combined therapy of sodium butyrate and docetaxel additively inhibits proliferation and promotes apoptosis of A549 lung adenocarcinoma cells via suppressing Gli1 expression in vitro and in vivo. Targeting Gli1 by the combined therapy may provide new insights into the therapeutic management of patients with lung adenocarcinoma.

Prevalence of postmastectomy pain syndrome and associated risk factors: A large single-institution cohort study.

Postmastectomy pain syndrome (PMPS) is a frequent complication of breast surgery, and is considered a chronic neuropathic pain in the side of surgery which persists more than 3 months. We conducted a retrospective analysis of the largest reported cohort to investigate the prevalence of PMPS and to analyze its associated risk factors as well as the influence on quality of life (QoL). Two thousand thirty-three surgically-treated female patients diagnosed between 2012 and 2017 with early-stage breast cancer were asked to complete a questionnaire survey about their current chronic neuropathic pain problems and quality of life. Multivariate logistic regression analyses were applied to determine the associated risk factors of PMPS. Results have shown that 1983 (97.5%) patients responded and completed a questionnaire survey. Among them, PMPS was found in 28.2% of patients. In univariate analysis, age≤35 years, tumor staging, history of chronic pain, total mastectomy, and axillary lymph node dissection (ALND) were significantly correlated with PMPS (P < .05). Multivariate analysis showed that age≤35 years, history of chronic pain, total mastectomy, and ALND were the independent risk factors of PMPS. QoL outcomes have shown that the global QoL score, physical function score, role function score, and social function score in the PMPS group were reduced in the PMPS group (P < .05), while the difference in emotional function score and cognitive function score showed no statistical significance (P > .05). Besides, patients with PMPS have worse body image, sexual enjoyment, and more breast symptoms. In conclusion, PMPS is linked with a high incidence among breast cancer patients, and has a considerable negative influence on the quality of life. In addition, age, total mastectomy, ALND, and history of chronic pain are the independent risk factors of PMPS.

Selective degradation of IKKα by autophagy is essential for arsenite-induced cancer cell apoptosis.

Two catalytic subunits of the IKK complex, IKKα and IKKß, trigger NF-κB activation as well as NF-κB-independent signaling events under both physiological and pathological conditions. Here we identified the NF-κB-unrelated cytoprotective function of IKKα in promoting autophagy by triggering p53 transactivation and upregulation of its downstream autophagic mediator, DRAM1, in the arsenite-treated hepatoma cells, which responses depended on IKKα kinase activity. Furthermore, IKKα triggered p53/DRAM1-dependent autophagy by inducing CHK1 activation and CHK1/p53 interaction. Interestingly, after provoking autophagy, IKKα could be specifically recognized by the autophagic machinery via directly binding with LC3B, resulting in selective degradation of IKKα by autophagy. Unexpectedly, the selectivity of autophagic sequestration towards IKKα was mediated by novel mechanism independent of the classical LC3-interacting regions (LIRs) within IKKα, while C-terminal arm of LIR was involved in mediating IKKα/LC3B interaction. Taken together, we conclude that IKKα attenuates arsenite-induced apoptosis by inducing p53-dependent autophagy, and then selective feedback degradation of IKKα by autophagy contributes to the cytotoxic response induced by arsenite.

ZBTB7A promotes migration, invasion and metastasis of human breast cancer cells through NF-κB-induced epithelial-mesenchymal transition in vitro and in vivo.

It has been generally confirmed that zinc finger and BTB domain containing 7A (ZBTB7A) plays an important role in the occurrence and progression of malignant tumours, but the promotion or inhibition effect is related to tumour type. The mechanism between ZBTB7A and breast cancer is not well understood, so further research is needed. In this study, we first investigated the expression of ZBTB7A in tissue samples of clinical breast cancer patients, MDA-MB-231, MCF-7 and MCF-10A cells. Second, we overexpressed the ZBTB7A in MCF-7 cells and silenced the ZBTB7A in MDA-MB-231 cells using lentivirus transfection technology, respectively, and verified the effect of ZBTB7A on migration and invasion of breast cancer cell lines through in vitro cell function experiments, such as wound-healing assay, migration and invasion assay, quantitative real time reverse transcriptase (qRT-PCR) and western blot. Then, the correlation between the above influences, epithelial-mesenchymal transition (EMT) and NF-κB was analysed. Finally, in vivo tumour transplantation model in nude mice was established to verified the effect of ZBTB7A on metastasis of breast cancer MDA-MB-231 cells. In conclusion, ZBTB7A is highly expressed in cancer tissue, breast cancer cell line MDA-MB-231 and MCF-7. Meanwhile, the high expression of ZBTB7A may promote cell migration, invasion and tumour metastasis, which may be related to EMT events by regulating NF-κB.

Triptolide Suppresses Growth of Breast Cancer by Targeting HMGB1 in Vitro and in Vivo.

Triptolide has been indicated potent anti-cancer effect involving multiple molecular targets and signaling pathways. High-mobility group box 1 (HMGB1) is a highly conserved DNA-binding protein taking part in breast cancer development. The therapeutic effect of triptolide on HMGB1 has not been reported. Thus, our study aims to clarify the role of HMGB1 in triptolide-induced anti-growth effect on breast cancer in vitro and in vivo. We demonstrated that triptolide significantly suppressed growth of breast cancer cells by inhibition of cell viability, clonogenic ability. Further studies evidenced that triptolide treatment not only inhibited HMGB1 mRNA expression, but also decreased supernatant level of HMGB1 in vitro. In line with these observations, exogenous recombinant HMGB1 (rHMGB1) promoted cell proliferation of breast cancer, and triptolide reversed the rHMGB1-promoted proliferative effect. As well, triptolide enhanced the anti-proliferative activity of ethyl pyruvate (EP) (HMGB1 inhibitor). Furthermore, downstream correlation factors (Toll-like receptor 4 (TLR4) and phosphorylated-nuclear factor-kappaB (NF-κB) p65) of HMGB1 were significantly decreased in vitro after triptolide treatment. Consistantly, we confirmed that tumor growth was significantly inhibited after triptolide treatment in vivo. Meanwhile, immunohistochemical analyses showed that triptolide treatment significantly decreased the level of cytoplasmic HMGB1 and TLR4 expression, whereas the expression of NF-κB p65 was relatively higher in cytoplasm, and conversely lower in nucleus as compared to the control group. Collectively, these results demonstrate that triptolide suppresses the growth of breast cancer cells via reduction of HMGB1 expression in vitro and in vivo, which may provide new insights into the treament of breast cancer.