Evaluation of Male Breast Cancer and the Application of Sentinel Lymph Node Biopsy: A Multicenter Retrospective Study.

Sentinel lymph node biopsy (SLNB) is currently used as a routine treatment for patients with breast cancer. However, it may not be applicable for patients with male breast cancer (MBC), because they have notably different clinicopathological features from those occurring in females. There is a lack of evidence of SLNB application and safe exemption from axillary lymph node dissection (ALND) in patients with MBC. This study aimed to evaluate the application of SLNB to provide information for the standardized treatment of patients with MBC. The MBC patient records from 4 institutions ranging from January 2001 to November 2020 were retrospectively reviewed. There were 220 patients with MBC with a median age of 60 (range 24-88) years and an average tumor size of 2.3 cm (range 0.5 cm-6.5 cm). Sixty-six percent of patients underwent SLNB, and 39% of them showed positive results. A total of 157 patients underwent ALND, while only half of them had positive nodes, causing unnecessary complications. For patients in the clinical early stage, we found that the SLNB showed a noninferiority to the ALND treatment in DFS (P = .18) and OS (P = .055). In conclusion, there are certain obstacles to the broad application of SLNB due to the lower proportion of patients with clinically negative lymph nodes. However, it is undeniable that SLNB can safely and effectively exempt patients with MBC at early stage with clinically negative nodes from ALND to reduce subsequent complications. It is still an ideal criterion for the axillary staging of patients with MBC.

Circular RNA circ_IRAK3 contributes to tumor growth through upregulating KIF2A via adsorbing miR-603 in breast cancer.

BACKGROUND: Breast cancer (BC) threatens the health of women around the world. Researchers have proved that hsa_circ_0005505 (circ_IRAK3) facilitates BC cell invasion and migration, but the regulatory mechanisms of circ_IRAK3 in BC remain mostly unknown. We aim to explore a new mechanism by which circ_IRAK3 promotes BC progression. METHODS: Levels of circ_IRAK3, microRNA (miR)-603, and kinesin family member 2A (KIF2A) mRNA in BC tissues and cells were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The cell cycle progression, colony formation, and proliferation of BC cells were evaluated by flow cytometry, plate clone, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assays. The migration, invasion, and apoptosis of BC cells were determined by transwell or flow cytometry assays. Several protein levels were detected using western blotting. The targeting relationship between circ_IRAK3 or KIF2A and miR-603 was verified via dual-luciferase reporter assay. The role of circ_IRAK3 in vivo was verified by xenograft assay. RESULTS: We observed higher levels of circ_IRAK3 in BC tissues and cell lines than their respective controls. Functional experiments presented that circ_IRAK3 silencing induced BC cell apoptosis, curbed cell proliferation, migration, and invasion in vitro, and decreased tumor growth in vivo. Mechanistically, circ_IRAK3 could modulate kinesin family member 2A (KIF2A) expression through acting as a microRNA (miR)-603 sponge. miR-603 silencing impaired the effects of circ_IRAK3 inhibition on the malignant behaviors of BC cells. Also, the repressive effects of miR-603 mimic on the malignant behaviors of BC cells were weakened by KIF2A overexpression. CONCLUSIONS: circ_IRAK3 exerted a promoting effect on BC progression by modulating the miR-603/KIF2A axis, providing a piece of novel evidence for circ_IRAK3 as a therapeutic target for BC.

Retrospective analysis: 5509 cases of "totally implantable venous access port systems implantation (TIVAPS) depth" assisted by digital radiography.

PURPOSE: Modern oncological treatment in breast cancer patients requires the precise delivery of chemotherapy infusion into the central venous systems without toxicity. TIVAPS is the significant method of chemotherapy delivery although certain internal or external complications associated with their placement. However, the long-term use of TIVAPS is still a concern to minimize the complications such as venous thrombosis syndrome (VTS) and cardiac defects. The aim of this study is to investigate the potential disadvantages that may be avoided by digital radiography (DR)-assisted measurement of catheter depth pertinent to TIVAPS implanted system. METHODS: Retrospective analysis related to 5509 TIVAPS recipients of 99% female breast cancer patients and 1% male blood disorder patients registered from April 2013 to November 2017 were included in the study. Patients with TIVAPS catheter tip depth into superior vena cava into upper (group A), middle (group B), and lower (group C) parts were stratified for evaluation during implantation; DR-assisted measurement of TIVAPS was performed to decipher "tip depth of catheter" and determined the relevance of tip depth to complications such as VTS and cardiac defects. RESULTS: Incidence of VTS complications were significantly higher in TIVAPS recipients of group A (82.7%) than group B (16%) and group C (0.12%) in which the "tip depth of TIVAPS was deeper" (P < 0.01). Defects in heart function are higher in group C (59.6%) than group A (15.8%) and group B (24.6%) in which the "tip depth of TIVAPS was deeper" (P < 0.01). CONCLUSION: DR-assisted measurement can more accurately determine the depth of TIVAPS catheter implantation, and avoid the incidence of related complications, and provide a better method for surgeons.

Hsa_circRNA_102229 facilitates the progression of triple-negative breast cancer via regulating the miR-152-3p/PFTK1 pathway.

BACKGROUND: Increasing evidence has suggested that circular RNAs (circRNAs) may act as an important regulatory factor in tumor progression. However, how circRNAs exert their functions in triple-negative breast cancer (TNBC) remains not clearly understood. METHODS: First, circRNA microarrays were conducted to identify aberrantly expressed circRNAs in TNBC tissues. Kaplan-Meier survival analysis was conducted to calculate the correlation between the level of hsa_circRNA_102229 and outcomes of patients with TNBC. The effect of hsa_circRNA_102229 and serine/threonine-protein kinase PFTAIRE 1 (PFTK1) on TNBC cells was clarified by cell counting kit-8, transwell and wound healing assays, as well as by a flow cytometry. The molecular mechanism of hsa_circRNA_102229 was clarified through bioinformatics, a dual-luciferase reporter assay, western blotting, fluorescence in situ hybridization and real-time polymerase chain reaction. Tumor xenograft experiments were performed to analyze growth and metastasis of TNBC in vivo. RESULTS: In TNBC tissues and cells, hsa_circ_102229 was remarkably up-regulated. Patients with TNBC presenting high hsa_circ_102229 exhibited poor prognosis. Moreover, hsa_circ_102229 could promote the migration, proliferation and invasion, whereas it inhibited the apoptosis of TNBC cells. Furthermore, hsa_circ_102229 directly targeted miR-152-3p and could regulate the expression of PFTK1 by targeting miR-152-3p. Rescue assays suggested that hsa_circ_102229 may exert its function in TNBC cells by regulating PFTK1. Additionally, knockdown of hsa_circ_102229 slowed down TNBC tumorigenesis and lung metastasis in a tumor xenograft animal model. CONCLUSIONS: Hsa_circ_102229 might serve as a competing endogenous RNA (ceRNA) to modulate PFTK1 expression via regulating miR-152-3p to affect the functions of TNBC cells. Hsa_circ_102229 acts as a newly discovered biomarker for TNBC treatment.

CircNOL10 suppresses breast cancer progression by sponging miR-767-5p to regulate SOCS2/JAK/STAT signaling.

BACKGROUND: Circular RNAs (circRNAs) have caught increasing attentions and interests for their important involvement in cancer initiation and progression. This study aims to investigate the biological functions of circNOL10 and its potential molecular mechanisms in breast cancer (BC). MATERIALS AND METHODS: qRT-PCR and western blot assays were performed to measure the expression of related genes. CCK-8, colony formation, flow cytomerty and transwell assays were used to assess cell proliferation, cell cycle, migration and invasion. RNA pull-down, luciferase reporter and RIP assays were applied to address the potential regulatory mechanism of circNOL10. RESULTS: CircNOL10 was down-regulated in BC tissues and cells. Low expression of circNOL10 was associated with larger tumor size, advanced TNM stage, lymph node metastasis and unfavorable prognosis. Overexpression of circNOL10 inhibited cell proliferation, migration, invasion and EMT in vitro and slowed xenograft tumor growth in vivo. Mechanistically, circNOL10 could act as a molecular sponge for miR-767-5p, leading to the up-regulation of suppressors of cytokine signaling 2 (SOCS2) and inactivation of JAK2/STAT5 pathway. Moreover, circNOL10-mediated suppression of malignant phenotypes was attenuated by miR-767-5p. Similar to circNOL10, enforced expression of SOCS2 also resulted in the suppression of cell proliferation and metastasis. Furthermore, knockdown of SOCS2 reversed the tumor-suppressive effect induced by circNOL10. CONCLUSIONS: CircNOL10 repressed BC development via inactivation of JAK2/STAT5 signaling by regulating miR-767-5p/SOCS2 axis. Our findings offer the possibility of exploiting circNOL10 as a therapeutic and prognostic target for BC patients.

Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation.

Sonic hesgehog (Shh) signaling has been reported to play an essential role in cancer progression. The mechanism of Shh involved in breast cancer carcinogenesis remains unclear. The present study sought to explore whether Shh signaling could regulate the glycolytic metabolism in breast cancers. Overexpression of the smoothed (Smo) and Gli-1 was found in human primary breast cancers. The expressions of Shh and Gli-1 correlated significantly with tumor size and tumor stage. In vitro, human recombinant Shh (rShh) triggered Smo and Gli-1 expression, promoted glucose utilization and lactate production, and accelerated cell proliferation in MCF-7 and MDA-MB-231 cells. Notably, rShh did not alter 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) expression but augmented PFKFB3 phosphorylation on ser(461), along with elevated fructose-2,6-bisphosphate (F2,6BP) generation by MCF-7 and MDA-MB-231 cells. This effect could be dampened by Smo siRNA but not by Gli-1 siRNA. In addition, our data showed the upregulated expressions of MAPK by rShh and elevatory PFKFB3 phosphorylation by p38/MAPK activated kinase (MK2). In conclusion, our study characterized a novel role of Shh in promoting glycolysis and proliferation of breast cancer cells via PFKFB3 phosphorylation, which was mediated by Smo and p38/MK2.

Overexpression of miR-206 suppresses glycolysis, proliferation and migration in breast cancer cells via PFKFB3 targeting.

miRNAs, sorting as non-coding RNAs, are differentially expressed in breast tumor and act as tumor promoters or suppressors. miR-206 could suppress the progression of breast cancer, the mechanism of which remains unclear. The study here was aimed to investigate the effect of miR-206 on human breast cancers. We found that miR-206 was down-regulated while one of its predicted targets, 6-Phosphofructo-2-kinase (PFKFB3) was up-regulated in human breast carcinomas. 17ß-estradiol dose-dependently decreased miR-206 expression as well as enhanced PFKFB3 mRNA and protein expression in estrogen receptor α (ERα) positive breast cancer cells. Furthermore, we identified that miR-206 directly interacted with 3'-untranslated region (UTR) of PFKFB3 mRNA. miR-206 modulated PFKFB3 expression in MCF-7, T47D and SUM159 cells, which was influenced by 17ß-estradiol depending on ERα expression. In addition, miR-206 overexpression impeded fructose-2,6-bisphosphate (F2,6BP) production, diminished lactate generation and reduced cell proliferation and migration in breast cancer cells. In conclusion, our study demonstrated that miR-206 regulated PFKFB3 expression in breast cancer cells, thereby stunting glycolysis, cell proliferation and migration.

Evaluation of miRNA-binding-site SNPs of MRE11A, NBS1, RAD51 and RAD52 involved in HRR pathway genes and risk of breast cancer in China.

MiRNA-binding-site single nucleotide polymorphisms (SNPs) in homologous recombination repair (HRR) pathway genes may change DNA repair capacity and affect susceptibility to cancer though complex gene-gene and gene-reproductive factors interactions. However, these SNPs associated with breast cancer (BC) are still unclear in Chinese women. Therefore, we conducted a case-control study to evaluate the genetic susceptibility of the five miRNA-binding-site SNPs in HRR pathway genes (MRE11A rs2155209, NBS1 rs2735383, RAD51 rs963917 and rs963918 and RAD52 rs7963551) in the development of BC. MRE11A rs2155209 and RAD52 rs7963551 were found to be associated with BC risk (ORadjusted: 1.87; 95 % CI: 1.23-2.86 and ORadjusted: 0.36; 95 % CI: 0.24-0.58). NBS1 rs2735383, RAD51 rs963917 and rs963918 were associated with BC risk after stratification according to reproductive factors. Haplotypes of Crs963917Ars963918 decreased the risk of BC (ORadjusted: 0.53; 95 % CI: 0.4-0.68), while the Trs963917Ars963918 and Trs963917Grs963918 haplotypes could increase the risk of BC (ORadjusted: 1.28; 95 % CI: 1.05-1.57 and ORadjusted: 1.31; 95 % CI: 1.09-1.62). Combined effect of risk alleles showed that the five SNPs were associated with increased BC risk in a dose-dependent manner (P trend = 0.003). The GC genotype of rs2735383, AG + GG genotype of rs963918 and AC + CC genotype of rs7963551 were associated with PR positivity of BC patients. These findings suggest that the miRNA-binding-site SNPs involved in HRR pathway genes may affect susceptibility of BC in Chinese women; moreover, the interactions of gene-gene and gene-reproductive factors play vital roles in the progression of BC. Further functional studies with larger sample are needed to support and validate these findings.

LncRNA LINC00649 promotes the growth and metastasis of triple-negative breast cancer by maintaining the stability of HIF-1α through the NF90/NF45 complex.

There is no clear treatment guideline or individualized treatment plan for triple-negative breast cancer (TNBC). The aim of this study was to investigate more effective targets for TNBC-targeted therapy. MDA-MB-231 and BT549 cell lines were used to explore the function of LINC00649 on the proliferation, invasion, and migration of TNBC cells. A mice subcutaneous tumor model and a pulmonary metastasis model was established to identify the role of LINC00649 on the growth and metastasis of TNBC in vivo. LINC00649 was found to be a key molecule involved in the occurrence and development of TNBC by screening of public databases and detection of TNBC clinical samples. LINC00649 increased hypoxia-inducible factor 1α (HIF-1α) mRNA stability and protein expression by interacting with the nuclear factor 90 (NF90)/NF45 complex. In vitro, interference with LINC00649 inhibits MDA-MB-231 and BT549 cell proliferation, migration, and invasion, and the addition of HIF-1α revised this effect. In vivo experiments showed that LINC00649 promoted the growth and metastasis of TNBC. We demonstrated that LINC00649 interacts with the NF90/NF45 complex to increase the mRNA stability of HIF-1α and up-regulate HIF-1α expression, thereby inducing the proliferation, invasion, and migration of TNBC cells as well as tumor growth and metastasis.

A Novel Nomogram for Predicting Breast Cancer-specific Survival in Male Patients.

OBJECTIVES: To compare breast cancer-specific survival (BCSS) of nonmetastatic invasive breast cancer between male (MBC) and female (FBC) patients, define clinicopathologic variables related to BCSS in nonmetastatic invasive MBC patients, and establish a nomogram for individual risk prediction. MATERIALS AND METHODS: On the basis of Surveillance, Epidemiology, and End Results database, 2094 MBC and 48,104 FBC cases underwent propensity score matching (PSM). We compared the prognosis of patients before and after PSM and developed a nomogram for BCSS of nonmetastatic invasive MBC patients. Internal validation was performed using the consistency index, calibration curves, and receiver operating characteristic curves. Simultaneously, data from 49 nonmetastatic invasive MBC patients diagnosed between January 2012 and May 2016 were collected for external validation. RESULTS: Before PSM, overall survival and BCSS were significantly shorter in MBC than those in FBC patients. After PSM, MBC patients continued to have a shorter overall survival, but not BCSS, than FBC patients. Marital status, age, histologic grade, estrogen/progesterone receptor status, Tumor Lymph Node stage, and surgery were included in the prediction model. CONCLUSIONS: The nomogram developed in this study seems to be more accurate than conventional Tumor-nodal-metastasis staging staging to predict BCSS and may serve as an effective tool for assessing the prognosis of nonmetastatic invasive MBC.

Pyrotinib-Containing Neoadjuvant Therapy in Patients With HER2-Positive Breast Cancer: A Multicenter Retrospective Analysis.

Background: Pyrotinib, a small-molecule tyrosine kinase inhibitor, has been investigated as a component of neoadjuvant therapy in phase 2 trials of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study aimed to evaluate the effectiveness and safety of pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer in the real-world setting. Methods: Data of 97 patients with HER2-positive breast cancer from 21 centers across China treated with pyrotinib-containing neoadjuvant therapy were reviewed. Neoadjuvant therapy consisted of taxane/carboplatin/trastuzumab plus pyrotinib (TCbH+Py, 30 [30.9%]), anthracycline/cyclophosphamide followed by taxane/trastuzumab plus pyrotinib (AC-TH+Py) or taxane followed by anthracycline/cyclophosphamide/trastuzumab plus pyrotinib (T-ACH+Py, 29 [29.9%]), taxane/trastuzumab plus pyrotinib (TH+Py, 23 [23.7%]), and other pyrotinib-containing neoadjuvant treatment (15 [15.5%]). The primary outcome was breast pathological complete response (bpCR, ypT0/is) rate. Secondary outcomes included total pathological complete response (tpCR, ypT0/is ypN0) rate, objective response rate (ORR), and the incidence of preoperative adverse events. Results: The ORR of pyrotinib-containing neoadjuvant therapy was 87.6% (85/97). The bpCR and tpCR rates were 54.6% (95% confidence interval [CI], 44.2%-64.7%) and 48.5% [95% CI, 38.2%-58.8%], respectively. The most common grade 3 or 4 treatment-related adverse events included diarrhea (15 [15.5%]), decreased hemoglobin (nine [9.3%]), and decreased neutrophil count (eight [8.2%]). No treatment-related deaths occurred. Conclusion: Pyrotinib-containing neoadjuvant therapy for patients with HER2-positive early or locally advanced breast cancer shows favorable effectiveness with manageable toxicity in the real-world setting. Trastuzumab plus pyrotinib may be a novel option of dual HER2-targeted blockade.

Patient Management Strategies in Perioperative, Intraoperative, and Postoperative Period in Breast Reconstruction With DIEP-Flap: Clinical Recommendations.

BACKGROUND AND OBJECTIVE: Deep Inferior Epigastric Perforator (DIEP) flap is a tissue isolated from the skin and subcutaneous tissue of the lower abdomen or rectus muscle to foster breast reconstruction. There is limited information about DIEP-flap induced complications associated with breast reconstruction surgery. EVIDENCE: We conducted a systematic review of the published literature in the field of breast cancer reconstruction surgery. Information was gathered through internet resources such as PubMed, Medline, eMedicine, NLM, and ReleMed etc. The following key phrases were used for effective literature collection: "DIEP flap", "Breast reconstruction", "Patient management", "Postoperative DIEP", "Intraoperative anticoagulant therapy", "Clinical recommendations". A total of 106 research papers were retrieved pertaining to this systematic review. CONCLUSION: A successful breast reconstruction with DIEP-flap without complications is the priority achievement for this surgical procedure. This study provides various evidence-based recommendations on patient management in the perioperative, intraoperative, and postoperative periods. The clinical recommendations provided in this review can benefit surgeons to execute breast reconstruction surgery with minimal postoperative complications. These recommendations are beneficial to improve clinical outcomes when performing surgery by minimizing complications in perioperative, intraoperative, and postoperative period.

Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU).

Emerging evidence has declared that Proteasome 26S subunit ATPase 2 (PSMC2) is involved in tumor progression. However, its role in breast cancer has not been investigated. Therefore, we sought to establish a correlation between breast cancer and PSMC2. PSMC2 expression in tissues was detected by immunohistochemistry. Loss-of-function study was used to evaluate the effects of PSMC2 knockdown in cell proliferation, apoptosis and migration. A gene microarray was performed to explore the potential downstream of PSMC2 with the help of Ingenuity Pathway Analysis (IPA). The effects of the PSMC2/PLAU axis on breast cancer were examined in vitro. Compared to para-cancer tissues, PSMC2 level was considerably elevated in breast cancer, which was significantly correlated with tumor grade. Knockdown of PSMC2 suppressed breast cancer progression in vitro and in vivo. The mechanistic research revealed that PSMC2 promotes the development and progression of human breast cancer through interacting with PLAU. Outcomes of our study showed that overexpression of PSMC2 provide tumorigenic and metastatic advantages in breast cancer, which may involve the regulation of PLAU. This study not only reveals a critical mechanism of breast cancer development, but also provides a promising therapeutic target for breast cancer treatment.

Totally Implantable Venous Access Port Systems: Implant Depth-based Complications in Breast Cancer Therapy - A Comparative Study.

BACKGROUND: Totally implantable venous access port system (TIVAPS) is widely used in breast cancer therapy; TIVAPS has several associated complications depending on the depth of implantation in breast cancer (BC) patients during continuous infusional chemotherapy regimens. The purpose of this study is to find out the optimal depth of TIVAPS implantation to reduce the incidence of complications during infusional chemotherapy. METHODS: This study reviewed the depth of TIVAPS implantation in the internal jugular vein in 1282 breast cancer patients over a ten-year period (2009-2019), and associated complications. We segregated the patients as 5 groups: 'Group A (depth < 4 mm), Group B (depth of 4-8 mm), Group C (depth of 8-12 mm), and Group D (depth of 12-16 mm), and Group E (depth of > 16 mm)'. Consequently, the 'internal complications' such as infection, venous thrombotic syndrome, catheter folding & migration, extravasation, whereas the 'external complications' viz., inflammation, local hematoma, local cutaneous reactions, and port exteriorization were significantly analyzed during TIVAPS implantation at different depths in BC patients. RESULTS: Overall incidence of 'internal complications' such as infections (8.6%, 2/23 cases), venous thrombotic syndrome (7.69%, 1/13 cases), catheter folding & migration (8.3%, 1/12 cases), and extravasation (8.3%, 1/12 cases) was comparatively lesser in Group C (8-12 mm) (p<0.01) than the Group A, Group B, Group D, and Group E respectively. Mainly, the external complications such as inflammation in Group C (8-12 mm) (pp< 0.01) was lesser (6.8%, 3/44 cases) than Group A, Group B, Group D, Group E. On the similar note, the local hematoma, and local cutaneous reaction, and port exteriorization were observed as '5% (1/20 cases), 4.2% (2/47 cases), and (3.2%, 1/31 cases)' in Group C patients (p<0.01), which were comparatively lesser than the other groups. CONCLUSION: Subcutaneous implantation of TIVAPS at a depth of 8-12 mm could be preferred due to the lowest incidence of internal and external complications compared to the incidence of these complications in other groups; this depth could be referred to as the safe and convenient implantation depth for the effective delivery of chemotherapy regimen in BC patients without difficulty in transcutaneous access to the port.

lncRNA GSEC Promotes the Progression of Triple Negative Breast Cancer (TNBC) by Targeting the miR-202-5p/AXL Axis.

BACKGROUND: This study aimed to explore the biological functions of G-quadruplex-forming sequence containing lncRNA (GSEC) in triple negative breast cancer (TNBC). METHODS: The expression of GSEC in TNBC tissues was evaluated by qRT-PCR. Cell viability was evaluated by Cell Counting Kit-8 assay. Cell proliferation was evaluated by 5-ethynyl-20-deoxyuridine (EdU) staining assay. Cell invasion and migration were evaluated by Transwell assay. Gain- and loss-function assays were performed to assess the biological functions of GSEC in TNBC. The interactions between GSEC, miR-202-5p and AXL were determined by luciferase report assay and RNA immunoprecipitation (RIP) assay. In addition, a nude mouse xenograft model was used to confirm the oncogenic role of GSEC in TNBC. RESULTS: GSEC was significantly upregulated in TNBC tissues and cancer cell lines, and high level of GSEC was associated with advanced tumor stage, positive lymph-node metastasis and the poor prognosis of TNBC patients. Knockdown of GSEC effectively inhibited TNBC cell proliferation, invasion and migration in vitro. GSEC regulated the expression of AXL by directly sponging miR-202-5p. Downregulation of miR-202-5p attenuated GSEC knockdown-induced inhibition on TNBC cell proliferation, invasion and migration in vitro. Meanwhile, overexpression of AXL obviously reversed the inhibitory effects of miR-202-5p mimics in TNBC progression in vitro. CONCLUSION: GSEC functioned as a potential oncogene and promoted AXL-mediated TNBC progression by sponging miR-202-5p, which might be a novel diagnostic and therapeutic target for TNBC.

LncRNA DLX6-AS1 Contributes to Epithelial-Mesenchymal Transition and Cisplatin Resistance in Triple-negative Breast Cancer via Modulating Mir-199b-5p/Paxillin Axis.

Triple-negative breast cancer (TNBC) is one of the most aggressive cancer types with high recurrence, metastasis, and drug resistance. Recent studies report that long noncoding RNAs (lncRNAs)-mediated competing endogenous RNAs (ceRNA) play an important role in tumorigenesis and drug resistance of TNBC. Although elevated lncRNA DLX6 antisense RNA 1 (DLX6-AS1) has been observed to promote carcinogenesis in various cancers, the role in TNBC remained unclear. In this study, expression levels of DLX6-AS1 were increased in TNBC tissues and cell lines when compared with normal tissues or breast fibroblast cells which were determined by quantitative real-time PCR (RT-qPCR). Then, CCK-8 assay, cell colony formation assay and western blot were performed in CAL-51 cells transfected with siRNAs of DLX6-AS1 or MDA-MB-231 cells transfected with DLX6-AS1 over expression plasmids. Knock down of DLX6-AS1 inhibited cell proliferation, epithelial-mesenchymal transition (EMT), decreased expression levels of BCL2 apoptosis regulator (Bcl-2), Snail family transcriptional repressor 1 (Snail) as well as N-cadherin and decreased expression levels of cleaved caspase-3, γ-catenin as well as E-cadherin, while up regulation of DLX6-AS1 had the opposite effect. Besides, knockdown of DLX6-AS1 in CAL-51 cells or up regulation of DLX6-AS1 in MDA-MB-231 cells also decreased or increased cisplatin resistance of those cells analyzed by MTT assay. Moreover, by using dual luciferase reporter assay, RNA immunoprecipitation and RNA pull down assay, a ceRNA which was consisted by lncRNA DLX6-AS1, microRNA-199b-5p (miR-199b-5p) and paxillin (PXN) was identified. And DLX6-AS1 function through miR-199b-5p/PXN in TNBC cells. Finally, results of xenograft experiments using nude mice showed that DLX6-AS1 regulated cell proliferation, EMT and cisplatin resistance by miR-199b-5p/PXN axis in vivo. In brief, DLX6-AS1 promoted cell proliferation, EMT, and cisplatin resistance through miR-199b-5p/PXN signaling in TNBC in vitro and in vivo.

The Long Non-coding RNA LINC01705 Regulates the Development of Breast Cancer by Sponging miR-186-5p to Mediate TPR Expression as a Competitive Endogenous RNA.

Long non-coding RNAs (lncRNAs) may be a regulatory factor of tumorigenesis. However, it is unclear what its biomechanisms are in breast cancer. In this study, different lncRNAs were detected in breast cancer through microarray analysis (GSE119233) and LINC01705 was selected for further study. qRT-PCR was then utilized for the detection of LINC01705 expression in breast cancer cells. A transwell assay, flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), a cell counting Kit-8 (CCK-8), and a wound-healing assay were performed to determine cell migration, invasion, apoptosis, and proliferation in breast cancer, respectively. For the identification of potential targets of LINC01705, dual-luciferase reporter gene and bioinformatics assays were conducted. Moreover, for the clarification of their interaction and roles in the regulation of the occurrence of breast cancer, Western blotting and RIP assays were conducted. Our findings revealed high LINC01705 expression in breast cancer tissues relative to adjacent non-cancerous tissues (n = 40, P < 0.001). Overexpression of LINC01705 notably enhanced cell migration and proliferation in breast cancer. In addition, LINC01705 positively regulated the translocated promoter region, nuclear basket protein (TPR) through competition with miR-186-5p. In conclusion, our results suggest that LINC01705 is implicated in the progression of breast cancer via competitively binding to miR-186-5p as a competing endogenous RNA (ceRNA), thereby regulating TPR expression.

Targeted Intraoperative Radiotherapy Is Non-inferior to Conventional External Beam Radiotherapy in Chinese Patients With Breast Cancer: A Propensity Score Matching Study.

Purpose: To investigate the efficacy of targeted intraoperative radiotherapy (TARGIT) vs. conventional external beam radiotherapy (EBRT) in Chinese patients with breast cancer. Methods: We retrospectively analyzed breast cancer patients who underwent breast-conserving surgery (BCS) at our hospital between April 2009 and October 2017. Patients were divided into TARGIT group and EBRT group according to different radiotherapy methods. TARGIT was performed with low-energy X-rays emitted by the Intrabeam system to deliver a single dose of 20 Gy to the applicator surface. Propensity score matching was performed at 1:1. The Kaplan-Meier method was used to calculate the locoregional recurrence (LR), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) of the two groups, and the log-rank test was run to analyse between-group difference before and after matching. Results: A total of 281 patients were included, with a median follow-up of 43 months. Of them, 82 were included in the TARGIT group and 199 in the EBRT group. Using the risk-adapted approach, 6.1% of patients received supplemental EBRT in the TARGIT group. The 5-year LR rate was 3.2% in the TARGIT group and 3.1% in the EBRT group (P = 0.694), the 5-year DMFS rates were 100 and 96.7%, respectively (P = 0.157); the 5-year DFS rates were 96.8 and 94.2% (P = 0.604); and the 5-year OS rates were 97.6 and 97.8% (P = 0.862). After matching which eliminated interference from imbalanced baseline factors, 128 matched patients were analyzed by the Kaplan-Meier method. The 5-year LR rate was 2.3% in the TARGIT group and 1.6% in the EBRT group; the 5-year DMFS rates were 100 and 98.4%, respectively; the 5-year DFS rates were 97.7 and 98.4%; and the 5-year OS rates were 98.4 and 98.4% (P = 0.659, 0.313, 0.659, 0.987). There was no significant difference in efficacy between TARGIT group and EBRT group. Conclusion: TARGIT and EBRT have similar 5-year outcomes in selected Chinese breast cancer patients undergoing BCS, and it can be used as an effective alternative to standard therapy, with substantial benefits to patients. The results need to be further confirmed by extending the follow-up time.

Upregulated Circular RNA circ-UBE2D2 Predicts Poor Prognosis and Promotes Breast Cancer Progression by Sponging miR-1236 and miR-1287.

Emerging evidence suggests that circular RNAs (circRNAs) are linked to the development and progression of human cancers. Nevertheless, their contribution to breast cancer (BC) is still largely unknown. In the current study, we screened and identified a novel circRNA, circ-UBE2D2, which was highly expressed in BC cell lines and tissues and was closely related to aggressive clinical features and dismal prognosis. Small interfering RNA (siRNA)-mediated circ-UBE2D2 silencing notably inhibited the proliferation, migration and invasion of BC cells, whereas circ-UBE2D2 overexpression displayed opposite effects. Mechanistically, circ-UBE2D2 was able to simultaneously function as molecular sponges of miR-1236 and miR-1287 to regulate the expression of their respective target genes. Moreover, circ-UBE2D2-induced tumor-promoting effects could be effectively blocked by miR-1236 or miR-1287 in BC cells. More importantly, therapeutic delivery of cholesterol-conjugated si-circ-UBE2D2 oligonucleotides significantly delayed tumor growth in vivo. Overall, our findings indicate that circ-UBE2D2 plays an essential oncogenic role in BC, and targeting circ-UBE2D2 may be a feasible treatment for BC patients.