Nrf2-mediated adenylosuccinate lyase promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma cells through ferroptosis escape.

Pancreatic cancer has one of the highest fatality rates and the poorest prognosis among all cancer types worldwide. Gemcitabine is a commonly used first-line therapeutic drug for pancreatic cancer; however, the rapid development of resistance to gemcitabine treatment has been observed in numerous patients with pancreatic cancer, and this phenomenon limits the survival benefit of gemcitabine. Adenylosuccinate lyase (ADSL) is a crucial enzyme that serves dual functions in de novo purine biosynthesis, and it has been demonstrated to be associated with clinical aggressiveness, prognosis, and worse patient survival for various cancer types. In the present study, we observed significantly lower ADSL levels in gemcitabine-resistant cells (PANC-1/GemR) than in parental PANC-1 cells, and the knockdown of ADSL significantly increased the gemcitabine resistance of parental PANC-1 cells. We further demonstrated that ADSL repressed the expression of CARD-recruited membrane-associated protein 3 (Carma3), which led to increased gemcitabine resistance, and that nuclear factor erythroid 2-related factor 2 (Nrf2) regulated ADSL expression in parental PANC-1 cells. These results indicate that ADSL is a candidate therapeutic target for pancreatic cancer involving gemcitabine resistance and suggest that the Nrf2/ADSL/Carma3 pathway has therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Outcomes of Breast-Conserving Therapy in Patients With Inflammatory Breast Cancer: A Meta-Analysis.

INTRODUCTION: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Currently, patients who respond to neoadjuvant chemotherapy (NAC) are treated with mastectomy and axillary lymph node dissection. This study aimed to synthesize real-world data to evaluate the feasibility of breast-conserving therapy (BCT), sentinel lymph node (SLN), and sentinel lymph node biopsy (SLNB) for patients with IBC who respond to NAC. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant articles. Clinical studies that compared mastectomy with BCT for IBC treatment were reviewed. The primary outcomes were local recurrence rate and 5-y survival rate in patients with IBC who responded to NAC. Furthermore, the SLN detection rate and false-negative rate (FNR) for SLNB were also evaluated. RESULTS: In the final analysis, 17 studies were included. The pooled estimates of the local recurrence rate for mastectomy and no surgical intervention were 18.6% and 15.9%, respectively (P = 0.956). Five-y survival was similar for mastectomy, partial mastectomy, and no surgical intervention (45.8%, 57.1%, and 39.4%, respectively). The pooled estimates of the SLN detection rate and FNR for SLNB were 81.9% and 21.8%, respectively. CONCLUSIONS: Among patients with IBC who respond to NAC, the local recurrence and 5-y survival rates in those undergoing BCT are noninferior to the rates in those undergoing mastectomy; therefore, BCT could be a feasible option for surgical management. However, a poor SLN detection rate and a high FNR were found in patients undergoing SLNB. Further large-scale clinical studies are required to confirm our findings.

Chaperone-mediated autophagy degrade Dicer to promote breast cancer metastasis.

Metastasis in breast cancer usually lead to the majority of deaths on clinical patients. Accordingly, diagnosis of metastasis at the early stage in breast cancer is important to improve the prognosis. We observed that Dicer protein levels are significant decrease in highly invasive breast cancer cells and usually correlated with poor clinical outcomes. Following, we aim to clarify the molecular regulatory mechanism of this phenomenon in breast cancer to provide a new therapeutic target. In this study, we obtained that Dicer expression correlated with metastasis and invasion without affect cell stability in breast cancer cells. Importantly, we identified the regulatory mechanism of Dicer protein degradation, the chaperone-mediated autophagy (CMA)-mediated degradation that is major mechanism to decrease Dicer protein expression and lead to cancer metastasis. We discovered that heat shock cognate 71-kDa protein (Hsc70) which as a CMA-related factor interacts with the CMA-targeting motif I333A/K334A on Dicer to promote degradation through CMA. Taken together, our findings hint that Dicer highly correlated with cancer metastasis, we reveal the tumor-promoting effect of CMA-mediated Dicer degradation in breast cancer.

Hypermethylation of TMEM240 predicts poor hormone therapy response and disease progression in breast cancer.

BACKGROUND: Approximately 25% of patients with early-stage breast cancer experience cancer progression throughout the disease course. Alterations in TMEM240 in breast cancer were identified and investigated to monitor treatment response and disease progression. METHODS: Circulating methylated TMEM240 in the plasma of breast cancer patients was used to monitor treatment response and disease progression. The Cancer Genome Atlas (TCGA) data in Western countries and Illumina methylation arrays in Taiwanese breast cancer patients were used to identify novel hypermethylated CpG sites and genes related to poor hormone therapy response. Quantitative methylation-specific PCR (QMSP), real-time reverse transcription PCR, and immunohistochemical analyses were performed to measure DNA methylation and mRNA and protein expression levels in 394 samples from Taiwanese and Korean breast cancer patients. TMEM240 gene manipulation, viability, migration assays, RNA-seq, and MetaCore were performed to determine its biological functions and relationship to hormone drug treatment response in breast cancer cells. RESULTS: Aberrant methylated TMEM240 was identified in breast cancer patients with poor hormone therapy response using genome-wide methylation analysis in the Taiwan and TCGA breast cancer cohorts. A cell model showed that TMEM240, which is localized to the cell membrane and cytoplasm, represses breast cancer cell proliferation and migration and regulates the expression levels of enzymes involved in estrone and estradiol metabolism. TMEM240 protein expression was observed in normal breast tissues but was not detected in 88.2% (67/76) of breast tumors and in 90.0% (9/10) of metastatic tumors from breast cancer patients. QMSP revealed that in 54.5% (55/101) of Taiwanese breast cancer patients, the methylation level of TMEM240 was at least twofold higher in tumor tissues than in matched normal breast tissues. Patients with hypermethylation of TMEM240 had poor 10-year overall survival (p = 0.003) and poor treatment response, especially hormone therapy response (p < 0.001). Circulating methylated TMEM240 dramatically and gradually decreased and then diminished in patients without disease progression, whereas it returned and its levels in plasma rose again in patients with disease progression. Prediction of disease progression based on circulating methylated TMEM240 was found to have 87.5% sensitivity, 93.1% specificity, and 90.2% accuracy. CONCLUSIONS: Hypermethylation of TMEM240 is a potential biomarker for treatment response and disease progression monitoring in breast cancer.

ERK-mediated transcriptional activation of Dicer is involved in gemcitabine resistance of pancreatic cancer.

Gemcitabine has been a commonly used therapeutic agent for treatment of pancreatic cancer. In the clinic, a growing resistance to gemcitabine has been observed in patients with pancreatic cancer, and investigation of the underlying mechanism of gemcitabine resistance is urgently required. The microRNA (miRNA)-producing enzyme, Dicer, is crucial for the maturation of miRNAs, and is involved in clinical aggressiveness, poor prognosis, and survival outcomes in various cancers, however, the role of Dicer in acquired gemcitabine resistance of pancreatic cancer is still not clear. Here, we found that Dicer expression was significantly increased in gemcitabine-resistant PANC-1 (PANC-1/GEM) cells compared with parental PANC-1 cells and observed a high level of Dicer correlated with increased risk of pancreatic cancer. Suppression of Dicer obviously decreased gemcitabine resistance in PANC-1/GEM cells; consistently, overexpression of Dicer in PANC-1 cells increased gemcitabine resistance. Moreover, we identified that transcriptional factor Sp1 targeted the promoter region of Dicer and found ERK/Sp1 signaling regulated Dicer expression in PANC-1/GEM cells, as well as positively correlated with pancreatic cancer progression and suggest that targeting the ERK/Sp1/Dicer pathway has potential therapeutic value for pancreatic cancer with acquired resistance to gemcitabine.

Axillary Management in Women with Early Breast Cancer and Limited Sentinel Node Metastasis: A Systematic Review and Metaanalysis of Real-World Evidence in the Post-ACOSOG Z0011 Era.

BACKGROUND: After the publication of the Z0011 trial, the American Society of Clinical Oncology published an updated clinical practice guideline stating that clinicians should not recommend axillary lymph node dissection (ALND) for early-stage breast cancer patients with the involvement of one or two sentinel lymph nodes (SLNs). However, these recommendations have been challenged because they were mainly based on data from limited studies. The aim of the current study is to systematically compare the real-world outcomes of SLN biopsy (SLNB) alone and SLNB + ALND in patients with early-stage breast cancers and limited positive SLN metastasis in the post-Z0011 era PATIENTS AND METHODS: We searched articles in the PubMed, EMBASE, and Cochrane library databases. The primary endpoints were overall survival (OS) and disease-free survival (DFS). The secondary endpoints were recurrence rate and the incidence of lymphedema. RESULTS: One randomized controlled trial and six retrospective studies with 8864 patients were retrieved. For patients with early-stage breast cancer with one or two SLN metastases, receiving SLNB alone showed no significant difference in OS, DFS, and recurrence rate compared with receiving SLNB + ALND. The incidence of lymphedema in patients who received SLNB alone was significantly lower than those who received SLNB + ALND (odds ratio 1.95, 95% confidence interval 1.02-3.71). CONCLUSIONS: Current real-world evidence proved that the Z0011 strategy is safe with respect to survival outcomes and effective in reducing the incidence of lymphedema. ALND should be avoided in patients with early-stage breast cancer with one or two SLN metastases in the post-Z0011 era.

4-Acetylantroquinonol B induced DNA damage response signaling and apoptosis via suppressing CDK2/CDK4 expression in triple negative breast cancer cells.

BACKGROUND: Triple-negative breast cancer (TNBC) has a more aggressive phenotype and poorer prognosis than hormone receptor (HR+) and human epidermal growth factor receptor (HER2 -) subtypes. Inhibition of cyclin-dependent kinase (CDK)4 and CDK6 was successful in patients with advanced metastatic HR+/HER2- breast cancer, but those with TNBC exhibited low or no response to this therapeutic approach. This study investigated the dual therapeutic targeting of CDK2 and CDK4 by using 4-acetyl-antroquinonol B (4-AAQB) against TNBC cells. METHODS: We examined the effects of CDK2, CDK4, and CDK6 inhibition through 4-AAQB treatment on TNBC cell lines and established an orthotropic xenograft mouse model to confirm the in vitro results of inhibiting CDK2, CDK4, and CDK6 by 4-AAQB treatment. RESULTS: High expression and alteration of CDK2 and CDK4 but not CDK6 significantly correlated with poor overall survival of patients with breast cancer. CDK2 and CDK4 were positively correlated with damage in DNA replication and repair pathways. Docking results indicated that 4-AAQB was bound to CDK2 and CDK4 with high affinity. Treatment of TNBC cells with 4-AAQB suppressed the expression of CDK2 and CDK4 in vitro. Additionally, 4-AAQB induced cell cycle arrest, DNA damage, and apoptosis in TNBC cells. In vivo study results confirmed that the anticancer activity of 4-AAQB suppressed tumor growth through the inhibition of CDK2 and CDK4. CONCLUSION: The expression level of CDK2 and CDK4 and DNA damage response (DDR) signaling are prominent in TNBC cell cycle regulation. Thus, 4-AAQB is a potential agent for targeting CDK2/4 and DDR in TNBC cells.

AXL is crucial for E1A-enhanced therapeutic efficiency of EGFR tyrosine kinase inhibitors through NFI in breast cancer.

AXL which is a chemosensitizer protein for breast cancer cells in response to epidermal growth factor receptor-tyrosine kinase inhibitor and suppresses tumor growth. The clinical information show nuclear factor I (NFI)-C and NFI-X expression correlate with AXL expression in breast cancer patients. Following, we establish serial deletions of AXL promoter to identify regions required for Adenovirus-5 early region 1A (E1A)-mediated AXL suppression. All of the NFI family members were extensively studied for their expression and functions in regulating AXL. Moreover, E1A post-transcriptionally downregulates AXL expression through NFI. NFI-C and NFI-X, not NFI-A and NFI-B, resulting in cell death in response to EGFR-TKI. Our finding suggests that NFI-C and NFI-X are crucial regulators for AXL and significantly correlated with poor survival of breast cancer patients.

Correction to: Axillary Management in Women with Early Breast Cancer and Limited Sentinel Node Metastasis: A Systematic Review and Metaanalysis of Real-World Evidence in the Post-ACOSOG Z0011 Era.

In the original version of the article, there was some misalignment of data in Table 1.

Vascular endothelial growth factor-C upregulates cortactin and promotes metastasis of esophageal squamous cell carcinoma.

BACKGROUND: Vascular endothelial growth factor-C (VEGF-C) plays an important role during cancer progression and metastasis through activation of VEGF receptors. However, the role of VEGF-C in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS: The expression of VEGF-C in advanced stages of esophageal cancer was examined by immunohistochemistry and its expression was correlated with the protein level of cortactin (CTTN) by Western blot. Knockdown and overexpression of the CTTN protein were respectively performed to investigate the effects on VEGF-C-enhanced ESCC migration/invasion by in vitro transwell assay, cell tracing assay, and tumor growth/experimental metastasis in animal models. RESULTS: The expression of VEGF-C was positively correlated with tumor status and poor clinical prognosis in patient with esophageal cancer. VEGF-C-upregulated CTTN expression contributed the migration/invasive abilities of ESCC cell lines through Src-mediated downregulation of miR-326. Moreover, knockdown of CTTN expression significantly abolished VEGF-C-induced tumor growth and experimental lung metastasis in vivo. CONCLUSIONS: Upregulation of CTTN is critical for VEGF-C-mediated tumor growth and metastasis of ESCC. These finding suggest that VEGF-C upregulated CTTN expression through Src-mediated downregulation of miR-326. CTTN may be a crucial mediator of VEGF-C-involved ESCC metastasis, which provides a potential target for diagnosis and individualized treatment in clinical practice.

Association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer: a meta-analysis.

Several previous studies have investigated the association between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer in various populations. However, these results remain inconsistent. Therefore, we performed this meta-analysis to evaluate the relationship between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer. An extensive literature search was performed to identify all eligible studies regarding this association. The odds ratios (ORs) with 95 % confidence intervals (CIs) were used to estimate the strength of risk under fixed and random effects models. We identified and included eight case-control studies including 2,036 cases and 2,273 controls. No significant association was found between the SULT1A1 Arg213His polymorphism and the risk of bladder cancer under the dominant model; however, those with the SULT1A1 Arg/Arg genotype had a significantly increased risk (OR = 1.218, 95 % CI = 1.067-1.392, P = 0.0044) under the recessive model. In the subgroup analysis of ethnicity, a significant association was observed in Caucasians under the recessive model (OR = 1.269, 95 % CI = 1.069-1.506, P = 0.007). Furthermore, an increased risk of bladder cancer was observed between the Arg213His polymorphism and never smokers in the recessive model (OR = 1.428, 95 % CI = 1.079-1.890, P = 0.013). The results of this meta-analysis indicate that the SULT1A1 Arg213His polymorphism is associated with the risk bladder cancer under a recessive model; however, a possibly higher risk for Caucasians with the Arg/Arg genotype and never smokers needs further investigation.

Hypermethylation of the Gene Body in SRCIN1 Is Involved in Breast Cancer Cell Proliferation and Is a Potential Blood-Based Biomarker for Early Detection and a Poor Prognosis.

Breast cancer is a leading cause of cancer mortality in women worldwide. Using the Infinium MethylationEPIC BeadChip, we analyzed plasma sample methylation to identify the SRCIN1 gene in breast cancer patients. We assessed SRCIN1-related roles and pathways for their biomarker potential. To verify the methylation status, quantitative methylation-specific PCR (qMSP) was performed on genomic DNA and circulating cell-free DNA samples, and mRNA expression analysis was performed using RT‒qPCR. The results were validated in a Western population; for this analysis, the samples included plasma samples from breast cancer patients from the USA and from The Cancer Genome Atlas (TCGA) cohort. To study the SRCIN1 pathway, we conducted cell viability assays, gene manipulation and RNA sequencing. SRCIN1 hypermethylation was identified in 61.8% of breast cancer tissues from Taiwanese patients, exhibiting specificity to this malignancy. Furthermore, its presence correlated significantly with unfavorable 5-year overall survival outcomes. The levels of methylated SRCIN1 in the blood of patients from Taiwan and the USA correlated with the stage of breast cancer. The proportion of patients with high methylation levels increased from 0% in healthy individuals to 63.6% in Stage 0, 80% in Stage I and 82.6% in Stage II, with a sensitivity of 78.5%, an accuracy of 90.3% and a specificity of 100%. SRCIN1 hypermethylation was significantly correlated with increased SRCIN1 mRNA expression (p < 0.001). Knockdown of SRCIN1 decreased the viability of breast cancer cells. SRCIN1 silencing resulted in the downregulation of ESR1, BCL2 and various cyclin protein expressions. SRCIN1 hypermethylation in the blood may serve as a noninvasive biomarker, facilitating early detection and prognosis evaluation, and SRCIN1-targeted therapies could be used in combination regimens for breast cancer patients.

Precise application of sentinel lymph node biopsy in patients with ductal carcinoma in situ: A systematic review and meta-analysis of real-world data.

PURPOSE: Although ductal carcinoma in situ (DCIS) seldom involves lymph nodes, some patients may upstage to invasive disease, thus requiring a second surgery for sentinel lymph node (SLN) biopsy (SLNB). However, the indications of SLNB remain inconclusive and clinical trials are rarely available. Our aim is to systematically review the real-world data to evaluate whether SLNB is precisely applied in patients with a high risk of upstaging from DCIS to invasive carcinoma. METHODS: PubMed, EMBASE, and Cochrane library databases were searched. Prospective and retrospective cohort studies that evaluated the pathological outcomes of SLNB and the upstaging rate in women with DCIS were included. The primary outcomes were the upstaging and SLN-positive rates of patients initially diagnosed as having DCIS. We analyzed factors, namely biopsy methods, clinical presentations, histological patterns, and hormone receptor status, that potentially indicate nodal involvement risk. RESULTS: We retrieved 43 prospective and 69 retrospective studies including 44,001 patients. The pooled estimates of upstaging and SLN-positive rates were 25.8% (95% confidence interval [CI]: 0.230-0.286) and 4.9% (95% CI: 0.042-0.055), respectively. In subgroup analysis, the upstaging rate was significantly higher in patients with estrogen receptor-negative status, palpable mass, tumor size >2 cm on imaging, and high-nuclear grade and those who received a preoperative diagnosis through core needle biopsy. CONCLUSION: The upstaging and SLN-positive rates of DCIS were 25.8% and 4.9%, respectively. By selecting patients with high risk DCIS, surgeons may increase the precision of and reduce the excess and incomplete treatment rates of SLNB.

Effect of patient decision aids on decisional conflict and regret associated with breast cancer surgery: a randomized controlled trial.

BACKGROUND: Patients with breast cancer encounter difficulties in making surgical treatment decisions. Shared decision-making (SDM) with patient decision aids (PDAs) can minimize patients' decisional conflicts. However, the effect of PDAs in Asia remains inconclusive. This study investigated the effect of SDM assisted by PDAs on the decisional conflict of patients with breast cancer. METHODS: In this two-group, outcome assessor-blind, randomized controlled trial, 151 patients diagnosed as having breast cancer were assigned to the PDA (SDM with PDA) group or the standard (SDM without PDA) group. Demographic and clinical variables were analyzed to identify variables affecting the treatment choice. The patients' decision-making difficulties were evaluated using the four-item SURE scale during preoperative hospitalization, and decisional conflicts were examined using the five-item Decision Regret scale and Hospital Anxiety and Depression Scale (HADS) 1 month after surgery. RESULTS: The choice of breast conservation therapy and mastectomy did not significantly differ between the PDA and standard groups. The PDA group had a higher level of depression after making decisions (P = 0.029) than did the standard group. No significant difference in the total scores of the SURE scale and Decision Regret scale were noted between the groups. CONCLUSION: PDAs did not assist the patients with breast cancer in making breast surgery-related decisions. Clinicians should focus on SDM grounded in evidence-based medicine with care and help patients consider their individual preferences. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03105076; April 7, 2017 ( http://www. CLINICALTRIALS: gov ).

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells.

Distant metastasis is the leading cause of death in patients with breast cancer. Despite considerable treatment advances, the clinical outcomes of patients with metastatic breast cancer remain poor. CSCs can self-renew, enhancing cancer progression and metastasis. Dicer, a microRNA (miRNA) processing-related enzyme, is required for miRNA maturation. Imbalanced Dicer expression may be pivotal in cancer progression. However, whether and how Dicer affects the stemness of metastatic breast cancer cells remains unclear. Here, we hypothesized that Dicer regulates the migration, invasion, and stemness of breast cancer cells. We established highly invasive cell lines (MCF-7/I-3 and MDA-MB-231/I-3) and observed that Dicer expression was conspicuously lower in the highly invasive cells than in the parental cells. The silencing of Dicer significantly enhanced the cell migratory/invasive abilities and CSCs properties of the breast cancer cells. Conversely, the overexpression of Dicer in the highly invasive cells reduced their migration, invasion, and CSCs properties. Our bioinformatics analyses demonstrated that low Dicer levels were correlated with increased breast cancer risk. Suppression of Dicer inhibited miR-200b expression, whereas miR-200b suppression recovered Dicer knockdown-induced migration, invasion, and cancer stem cells (CSCs) properties of the breast cancer cells. Thus, our findings reveal that Dicer is a crucial regulator of the migration, invasion, and CSCs properties of breast cancer cells and is significantly associated with poor survival in patients with breast cancer.

Promoter hypomethylation and overexpression of TSTD1 mediate poor treatment response in breast cancer.

Epigenetic alterations play a pivotal role in cancer treatment outcomes. Using the methylation array data and The Cancer Genome Atlas (TCGA) dataset, we observed the hypomethylation and upregulation of thiosulfate sulfurtransferase-like domain containing 1 (TSTD1) in patients with breast cancer. We examined paired tissues from Taiwanese patients and observed that 65.09% and 68.25% of patients exhibited TSTD1 hypomethylation and overexpression, respectively. A significant correlation was found between TSTD1 hypomethylation and overexpression in Taiwanese (74.2%, p = 0.040) and Western (88.0%, p < 0.001) cohorts. High expression of TSTD1 protein was observed in 68.8% of Taiwanese and Korean breast cancer patients. Overexpression of TSTD1 in tumors of breast cancer patients was significantly associated with poor 5-year overall survival (p = 0.021) and poor chemotherapy response (p = 0.008). T47D cells treated with TSTD1 siRNA exhibited lower proliferation than the control group, and transfection of TSTD1 in MDA-MB-231 induced the growth of MDA-MB-231 cells compared to the vector control. Additionally, overexpression of TSTD1 in MCF7 cells mediated a poor response to chemotherapy by epirubicin (p < 0.001) and docetaxel (p < 0.001) and hormone therapy by tamoxifen (p =0.025). Circulating cell-free hypomethylated TSTD1 was detected in plasma of Taiwanese breast cancer patients with disease progression and poor chemotherapy efficacy. Our results indicate that promoter hypomethylation and overexpression of TSTD1 in patients with breast cancer are potential biomarkers for poor 5-year overall survival and poor treatment response.

Cancer-Associated Exosomal CBFB Facilitates the Aggressive Phenotype, Evasion of Oxidative Stress, and Preferential Predisposition to Bone Prometastatic Factor of Breast Cancer Progression.

Background: Despite therapeutic advancements, metastasis remains a major cause in breast cancer-specific mortality. Breast cancer cells are susceptible to oxidative damage and exhibit high levels of oxidative stress, including protein damage, DNA damage, and lipid peroxidation. Some breast cancer risk factors may change the level of endogenous oxidative stress. Circulating exosomes play critical roles in tumorigenesis, distant metastasis, and poor prognosis in patients with breast cancer. Methods: We used an online database to analyze the expression and prognostic value of core binding factor subunit ß (CBFB) and oxidative stress-related targets in patients with breast cancer. Serum from healthy controls and patients with primary breast cancer or bone metastatic breast cancer in the bone was collected. Exosomes were isolated from the sera or cell culture media. We used an MDA-MB-436-innoculated tumor xenograft mouse model for silencing CBFB. Results: Circulating exosomes from patients with breast cancer metastasis to the bone were rich in CBFB. The human mammary fibroblast cells HMF3A and fibroblasts derived from patient samples cocultured with exosomes had increased α-SMA and vimentin expression and IL-6 and OPN secretion. Similarly, nonmetastatic breast cancer cells cocultured with exosomes exhibited increased levels of certain markers, including vimentin, snail1, CXCR4, and Runx2, and the exosomes had high CBFB expression. Silencing CBFB in metastatic MDA-MB-436 and MDA-MB-157 cells resulted in suppressed migration and invasion and downregulation of vimentin, CXCR4, snail1, Runx2, CD44, and OPN. Conversely, CBFB overexpression resulted in upregulation of Runx2, vimentin, snail1, CD44, and OPN in nonmetastatic T47D and MCF12A cells. The CBFB-rich exosomes derived from MDA-MB-436 cells induced enhanced metastatic phenotypes in the low-metastatic T47D and MCF12A cell lines. Conclusion: Our results revealed that CBFB may promote bone metastasis in patients with breast cancer. Of therapeutic relevance, targeting CBFB resulted in decreased tumor burden and bone metastasis, downregulation of bone metastasis markers, and impaired regulation of oxidative stress-related proteins NAE1 and NOS1.

Automatic Detection of the Circulating Cell-Free Methylated DNA Pattern of GCM2, ITPRIPL1 and CCDC181 for Detection of Early Breast Cancer and Surgical Treatment Response.

The early detection of cancer can reduce cancer-related mortality. There is no clinically useful noninvasive biomarker for early detection of breast cancer. The aim of this study was to develop accurate and precise early detection biomarkers and a dynamic monitoring system following treatment. We analyzed a genome-wide methylation array in Taiwanese and The Cancer Genome Atlas (TCGA) breast cancer (BC) patients. Most breast cancer-specific circulating methylated CCDC181, GCM2 and ITPRIPL1 biomarkers were found in the plasma. An automatic analysis process of methylated ccfDNA was established. A combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was performed in R using Recursive Partitioning and Regression Trees to establish a new prediction model. Combined analysis of CCDC181, GCM2 and ITPRIPL1 (CGIm) was found to have a sensitivity level of 97% and an area under the curve (AUC) of 0.955 in the training set, and a sensitivity level of 100% and an AUC of 0.961 in the test set. The circulating methylated CCDC181, GCM2 and ITPRIPL1 was also significantly decreased after surgery (all p < 0.001). The aberrant methylation patterns of the CCDC181, GCM2 and ITPRIPL1 genes means that they are potential biomarkers for the detection of early BC and can be combined with breast imaging data to achieve higher accuracy, sensitivity and specificity, facilitating breast cancer detection. They may also be applied to monitor the surgical treatment response.

Cryptanshinone Inhibits the Glycolysis and Inhibits Cell Migration Through PKM2/ß-Catenin Axis in Breast Cancer.

BACKGROUND: Breast cancer is one of the most prevalent gynecologic malignancies worldwide. Despite the high sensitivity in response to chemotherapy, drug resistance occurred frequently in clinical treatment. Cryptotanshinone (CTS) is a herbal medicine and has been identified as an anti-inflammatory and anti-oxidative drug. METHODS: In vitro assays, including the cell proliferation assay, colony formation assay, Western blot analysis, transwell migration/invasion assays, and cell scratch assay were used to explore the biological activities and working mechanism of CTS. Breast cancer cells were also transfected with PKM2 expressing vectors to define the molecular mechanisms involved in CTS-mediated anti-tumor activity. RESULTS: We found that CTS shows anti-proliferative effects and decreases the clonogenic ability of breast cancer cells. We also found that CTS inhibited the migration and invasion activity of MCF-7 and MDA-MB-231 cells by different analyzed methods. CTS also downregulated the levels of glycolysis-related proteins, such as PKM2, LDHA, and HK2. In addition, overexpression of PKM2 recovered CTS-mediated suppression of cell proliferation, colony formation, and cell mobility of breast cancer cells. We also found PKM2 was significantly overexpressed in tumor tissues and invasive ductal breast carcinoma compared to normal tissues and patients with high PKM2 expression had worse overall survival and metastasis-free survival outcomes. CONCLUSION: CTS inhibited the proliferation, migration, and invasion of breast cancer cells. The involved mechanism may refer to the downregulation of the PKM2/ß-catenin axis.

Effect of acupuncture on aromatase inhibitor-induced arthralgia in patients with breast cancer: A meta-analysis of randomized controlled trials.

PURPOSE: Aromatase inhibitor (AI)-induced arthralgia (AIA) is a common side effect that may lead to premature discontinuation of effective hormonal therapy in patients with breast cancer. Acupuncture may relieve joint pain in patients with AIA. We conducted a meta-analysis of randomized controlled trials (RCTs) to evaluate the effectiveness of acupuncture in pain relief in AIA. METHODS: The PubMed, Embase, Cochrane Library, and Scopus databases and the ClinicalTrials.gov registry were searched for studies published before February 2017. Individual effect sizes were standardized, and a meta-analysis was conducted to calculate the pooled effect size by using a random effect model. Pain was assessed using the Brief Pain Inventory (BPI) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 3-4, 6-8, and 12 weeks. Secondary outcomes included disability level, upper extremity function, physical performance, and quality of life. RESULTS: Five trials involving 181 patients were reviewed. Significant pain reduction was observed after 6-8 weeks of acupuncture treatment. Patients receiving acupuncture showed a significant decrease in the BPI worst pain score (weighted mean difference [WMD]: -3.81, 95% confidence interval [CI]: -5.15 to -2.47) and the WOMAC pain score (WMD: -130.77, 95% CI: -230.31 to -31.22) after 6-8 weeks of treatment. One of the 4 trials reported 18 minor adverse events in 8 patients during 398 intervention episodes. CONCLUSION: Acupuncture is a safe and viable nonpharmacologic treatment that may relieve joint pain in patients with AIA. Additional studies involving a higher number of RCTs are warranted.