Squalene epoxidase promotes breast cancer progression by regulating CCNB1 protein stability.

BACKGROUND: Breast cancer (BC) is a prevalent malignancy affecting women, characterized by a substantial occurrence rate. Squalene epoxidase (SQLE) is a crucial regulator of ferroptosis and has been associated with promoting cell growth and invasion in different types of human cancers. This study aimed to investigate the functional significance of SQLE in BC and elucidate the underlying molecular mechanisms involved. METHODS: SQLE expression levels in BC tissues were evaluated using quantitative real-time polymerase chain reaction, western blotting, and immunohistochemistry. Cell viability, invasion, migration, and cell cycle distribution were assessed using a combination of assays, including the Cell Counting Kit-8, EdU, colony formation, Transwell, and wound healing assays and flow cytometry analysis. Measurement of intracellular reactive oxygen species (ROS), malondialdehyde assay, and glutathione assay were utilized to investigate ferroptosis. Furthermore, co-immunoprecipitation and immunofluorescence assays were conducted to explore the correlation between SQLE and CCNB1. The in vivo tumor growth was evaluated by conducting a xenograft tumorigenicity assay to investigate the impact of SQLE. RESULTS: SQLE expression was significantly increased in BC, and higher SQLE expression levels were significantly associated with an unfavorable prognosis. In vitro functional assays revealed that the overexpression of SQLE markedly enhanced the proliferation, migration, and invasion capacities of BC cells. Furthermore, SQLE overexpression facilitated tumor growth in nude mice. Mechanistically, SQLE alleviated the ubiquitination modification of CCNB1, leading to enhanced stability of the CCNB1 protein and decreased intracellular ROS levels. Ultimately, this inhibited ferroptosis and facilitated the progression of BC. Our findings have provided insights into a crucial pathway by which elevated SQLE expression confers protection to BC cells against ferroptosis, thus promoting cancer progression. SQLE may serve as a novel oncological marker and a potential therapeutic target for BC progression. CONCLUSIONS: In conclusion, this study provides evidence that SQLE plays a regulatory role in BC progression by modulating CCNB1 and ferroptosis. These findings offer valuable insights into the role of SQLE in the pathogenesis of BC and demonstrate its potential as a therapeutic target for treating BC.

CircSNX25 mediated by SP1 promotes the carcinogenesis and development of triple-negative breast cancer.

Circular RNAs (circRNAs), according to a growing body of research, are thought to be important in the initiation and development of a number of cancers. However, more research is needed to fully understand how circRNAs work at the molecular level in triple-negative breast cancer (TNBC). RNA sequencing was conducted on four sets of TNBC samples and their corresponding adjacent noncancerous tissues (ANTs). The circSNX25 expression was assessed using quantitative real-time PCR in TNBC tissues and cells. Several in vitro and in vivo experiments were conducted in order to examine the function of circSNX25 in TNBC carcinogenesis. Through luciferase reporter and chromatin immunoprecipitation (ChIP) assays, we also investigated the potential regulation of circSNX25 biogenesis by specificity protein 1 (SP1). To further validate the relationship between circSNX25 and COPI coat complex subunit beta 1 (COPB1) in TNBC, we conducted circRNA pull-down and RNA immunoprecipitation (RIP) assays using the MS2/MS2-CP system. Online databases were analyzed to examine the clinical implications and prognostic value of COPB1 in TNBC. A higher circSNX25 expression levels were observed in tissues and cells of TNBC. Silencing circSNX25 notably inhibited TNBC cell proliferation, triggered apoptosis, and hindered tumor growth in vivo. Conversely, upregulation of circSNX25 had the opposite effects. Mechanistically, circSNX25 was found to physically interact with COPB1. Importantly, we identified that SP1 may enhance circSNX25 biogenesis. COPB1 levels were markedly higher in TNBC cells. Analysis of online databases revealed that TNBC patients with elevated COPB1 levels had a poorer prognosis. Our findings demonstrate that SP1-mediated circSNX25 promotes TNBC carcinogenesis and development. CircSNX25 may therefore serve as both a diagnostic and therapeutic biomarker for TNBC patients.

Molecular characteristics and prognosis of breast cancer patients with different level of HER2 positivity after adjuvant and neoadjuvant chemotherapy.

PURPOSE: HER2-low breast cancer (BC) has renewed interests of researchers worldwide. Here, we aimed to investigate the clinicopathological characteristics of patients with HER2-low, HER2-0 and HER2 ultra-low BC and make conclusion. METHODS: We collected cases of patients who were diagnosed as BC at Jingling General hospital. Immunohistochemistry was used to redefine HER2 scores. Kaplan-Meier methods and Cox proportional hazards regression analysis were used to compare survival. RESULTS: We found that HER2-low BC was more frequent in hormone receptor (HR)-positive BC patients and was associated with fewer T3-T4, lower breast conserving surgery rate and higher adjuvant chemotherapy rate. HER2-low BC patients had better overall survival (OS) compared to HER2-0 BC in premenopausal and stage II BC. Furthermore, HER2-0 BC patients had lower Ki-67 expression levels compared to HER2-ultra low and HER2-low BC in HR-negative BC. HER2-0 BC patients also had worse OS rate compared to those with HER2-ultra low BC in HR-positive BC. Finally, HER2-0 BC patients showed a higher pathological response rate compared to those with HER2-low BC after neoadjuvant chemotherapy. CONCLUSIONS: These findings suggest that HER2-low BC has distinct biology and clinical features compared to HER2-0 BC, and more investigation is needed to understand the biology of HER2-ultra low BC.

Polyamine synthesis enzyme AMD1 is closely related to the tumorigenesis and prognosis of human breast cancer.

Adenosylmethionine decarboxylase 1 (AMD1) has been implicated in carcinogenesis and tumor progression. However, the potential biomechanism and biological implications of AMD1 in breast cancer (BC) remain unclear. The purpose of this study was to investigate the effect of abnormal expression of AMD1 in BC. The expression of AMD1 in different human BC cell lines was studied by using western blotting and qRT-PCR. In vitro cell proliferation, clone formation, cell cycle and apoptosis assays were performed to explore the effect of AMD1 on cellular proliferation. Xenograft mouse models were established to elucidate the role of AMD1 in BC growth. The expression profiles of AMD1 in 28 pairs of BC tissues and adjacent noncancerous tissues (ANTs) were investigated by using western blotting and immunohistochemistry. The clinical implication and prognostic evaluation of AMD1 in BC were examined by excavating the online database. We found that the expression levels of AMD1 in BC cell lines were significantly higher than those in the normal human breast epithelial cell line MCF-10A. In addition, AMD1 potentiated proliferation, induced cell cycle progression and inhibited apoptosis in BC cells. Subcutaneous tumor xenografts also supported the promotive role of AMD1 in BC growth. We discovered that the level of AMD1 in BC tissues was significantly higher than that in ANTs. Using the online database, increased AMD1 was found to be associated with clinical indicators and predicted a poor prognosis in patients with BC. Our findings indicate that AMD1 elicits potent oncogenic effects on the malignant progression of BC. AMD1 might serve as a promising diagnostic biomarker and therapeutic target for patients with BC.

FZD2 promotes TGF-ß-induced epithelial-to-mesenchymal transition in breast cancer via activating notch signaling pathway.

BACKGROUND: Breast cancer (BC) is one of the commonest female cancers, which is characterized with high incidence. Although treatments have been improved, the prognosis of BC patients in advanced stages remains unsatisfactory. Thus, exploration of the molecular mechanisms underneath BC progression is necessary to find novel therapeutic methods. Frizzled class receptor 2 (FZD2) belongs to Frizzled family, which has been proven to promote cell growth and invasion in various human cancers. The purpose of our current study was to detect the functions of FZD2 in BC and explore its underlying molecular mechanism. METHODS: The level of FZD2 was measured in BC tissues by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, immunohistochemistry (IHC), respectively. Cell Counting Kit-8 (CCK-8), colony formation assay, transwell assays, wound healing assay and flow cytometry analyses were separately conducted to detect cell viability, invasion, migration, apoptosis and cell cycle distribution. The levels of Epithelial-mesenchymal transition (EMT) biomarkers were examined by using Immunofluorescence assay. Xenograft tumorigenicity assay was performed to assess the effect of FZD2 on tumor growth in vivo. RESULTS: FZD2 mRNA and protein expression was abundant in BC tissues. Moreover, high level of FZD2 had significant correlation with poor prognosis in BC patients. In vitro functional assays revealed that silencing of FZD2 had suppressive effects on BC cell growth, migration and invasion. Animal study further demonstrated that FZD2 silencing inhibited BC cell growth in vivo. In addition, FZD2 induced EMT process in BC cells in a transforming growth factor (TGF)-ß1-dependent manner. Mechanistically, knockdown of FZD2 led to the inactivation of Notch signaling pathway. CONCLUSION: FZD2 facilitates BC progression and promotes TGF-ß1-inudced EMT process through activating Notch signaling pathway.

Prognostic Value of Differentially Expressed LncRNAs in Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

Breast cancer is the most common cancer in women worldwide and can be classified into multiple subtypes, including triple-negative breast cancer (TNBC). TNBC is more aggressive than other types of breast cancer and has a poor prognosis. However, excluding chemotherapy, the treatment of TNBC does not involve targeted therapy. The dysregulated expression of lncRNAs plays a vital role in the development of numerous cancers. Thus, the aim of this meta-analysis is to determine the functional roles of lncRNAs in TNBC. We performed a systematic search for articles related to TNBC using multiple online databases, including PubMed, EMBASE, Web of Science, and Science-Direct. We collated pooled hazard ratios with 95% confidence interval to estimate the prognostic value of lncRNAs. We assessed the quality of studies using the Newcastle-Ottawa scale. Data were collected from cohort studies that compared overall survival, disease-free survival, and relapse-free survival between patients with high and patients with low expression of lncRNAs. Using 2,192 samples from 21 studies, we observed a correlation between poor prognosis and the upregulation of 14 lncRNAs (LINC00173, HUMT, HOTAIR, LUCAT1, HIF1A-AS2, ZEB2-AS1, NAMPT-AS, DANCR, LINC01638, ZNF469-3, AFAP1-AS1, ANRIL, MALAT1, and HULC) and downregulation of four lncRNAs (MIR503HG, NEF, TC0NS_12_00002973, and GAS5). The pooled hazard ratios for the correlation between differentially expressed lncRNAs and overall, disease-free, and relapse-free survival were 2.38 (2.03-2.78), 2.19 (1.51-3.16), and 3.19 (0.81-12.53), respectively. This meta-analysis shows that the expression of candidate lncRNAs may reliably predict the prognosis of patients with TNBC.

Postchemotherapy hippocampal functional connectivity patterns in patients with breast cancer: a longitudinal resting state functional MR imaging study.

The hippocampus plays a key role in cognitive function and emotion regulation due to its wide connection with the whole brain. This study examined the acute effect of chemotherapy on hippocampal and subfield functional connectivity and neuropsychological status in breast cancer patients (BC). This IRB approved study included 29 BC and 25 age matched healthy controls (HCs) who underwent resting state functional magnetic resonance imaging (Rs-fMRI), neuropsychological tests and blood examinations at baseline and one week after completing chemotherapy or in the same time interval. Within-group comparisons and group-by-time interactions analysis of hippocampus- and subregion- based functional connectivity were performed between the two groups. Functional connectivity changes were correlated with changes of blood examination and neuropsychological test scores in the BC group. The BC group had higher depression and anxiety scores, poorer performance on visual mobility, auditory memory and executive function than HCs (p < 0.05), and significantly abnormal estrodiol, total cholesterol and triglycerides (p < 0.05). BC survivors showed significant hippocampal functional connectivity changes mainly in the left insula, temporal lobe (Gaussian Random Field theory correction, P < 0.001) and the left inferior frontal gyrus (P < 0.01). The functional connections from the anterior hippocampus to the left temporal lobe were greater than the posterior hippocampus (P < 0.05). The hippocampus functional connectivity alterations were closely related to changes in depression scores, estrodiol and triglycerides (all p < 0.05). Chemotherapy induced especially anterior hippocampal functional connectivity abnormality, which is related to depression symptom, estrodiol and triglycerides disorders.

Downregulation of long non-coding RNA Opa interacting protein 5-antisense RNA 1 inhibits breast cancer progression by targeting sex-determining region Y-box 2 by microRNA-129-5p upregulation.

Several studies have shown an important role for long non-coding RNA (lncRNA) in breast cancer progression. The present study investigated the role of lncRNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) in the progression of breast cancer. OIP5-AS1 was significantly upregulated in breast cancer tissues and in breast cancer cell lines, and OIP5-AS1 downregulation inhibited the malignant behavior of breast cancer in vitro and in vivo. For in-depth exploration of the mechanism of OIP5-AS1 in breast cancer, we found that expression of microRNA-129-5p(miR-129-5p), which was found to bind sites in the sequence of OIP5-AS1, in breast cancer tissues was negatively correlated with OIP5-AS1. Also, luciferase assays indicated that OIP5-AS1 acted as a miR-129-5p sponge, resulting in upregulated expression of the sex-determining region Y-box 2 (SOX2) transcription factor. Our study showed that OIP5-AS1 plays a critical role in promoting breast cancer progression and that OIP5-AS1 downregulation targets SOX2 by miR-129-5p upregulation.

microRNA-129-5p suppresses Adriamycin resistance in breast cancer by targeting SOX2.

Adriamycin resistance is closely related to therapeutic efficacy in breast cancer patients and their prognosis. Increasing evidence has suggested that miRNA functions in Adriamycin resistance in various types of cancer. microRNA-129-5p (miR-129-5p) has been considered a tumor-suppressive miRNA in several cancers, but its potential role in Adriamycin resistance in breast cancer has not been fully elucidate. By qRT-PCR assay, we revealed that the expression of miR-129-5p was significantly decreased in breast cancer tissues and Adriamycin-resistant breast cancer cells (MDA-MB-231/ADR, MCF-7/ADR). CCK-8, colony formation, wound healing, Transwell invasion, and flow cytometric profiles were examined to determine the influence of miR-129-5p on Adriamycin-resistant breast cancer in vitro. The upregulation of miR-129-5p decreased the IC50 concentration of Adriamycin and invasion and promoted the apoptosis of MDA-MB-231/ADR cells in the presence of Adriamycin, whereas the upregulation of Sex-Determining Region Y-Box 2 (SOX2) reversed these effects. A luciferase reporter assay confirmed the binding of miR-129-5p to the 3'UTR of SOX2. Collectively, it was suggested that miR-129-5p suppresses Adriamycin resistance in breast cancer by directly targeting SOX2.

Expression of long non-coding RNA SNHG3 in breast cancer and its clinical significance / 医学研究生学报

ObjectiveThere are a few reports about the expression of SNHG3 in breast cancer and its effects. This study aimed to detect the expression of SNHG3 in breast cancer and paracancerous tissues, along with its relevance to clinicopathological parameters.MethodsSeventy-four patients with breast cancer were confirmed pathologically in our hospital from Jan. 2014 to Dec. 2017. The expression of SNHG3 was examined in breast cancer and paracancerous tissues by qRT-PCR. Correlations between the expression of SNHG3 and clinicopathological parameters were analyzed.Results SNHG3 expression was significantly downregulated in breast cancer tissues compared to paracancerous tissues, and the difference was of statistical significance (P<0.000). Low expression of SNHG3 was in negative correlation to Ki-67 (rs=-0.296, P=0.013).ConclusionThe expression of SNHG3 downregulated in breast cancer tissues, and its expression level is related to Ki-67, which may serve as a potential diagnostic molecular marker.