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.

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.