Poor Prognosis In Breast Cancer Patients Research Articles

MicroRNA-217 aggravates breast cancer through activation of NF1-mediated HSF1/ATG7 axis and c-Jun/ATF3/MMP13 axis.

Application of microRNA-mediated mRNA expression in treatment of diverse cancers has been documented. The current study was explored to study the role of miR-217 in breast cancer (BC) progression and the related downstream factors. Clinical tissue samples, BC cell lines and the established xenograft models were prepared for ectopic expression and depletion experiments to discern the regulatory roles of miR-217-mediated NF1 in BC cell proliferation, metastasis and chemoresistance as well as tumorigenic ability of BC cells in nude mice. miR-217 was upregulated in BC, which was a predictor of poor prognosis of BC patients. NF1 could be targeted by miR-217. miR-217 promoted malignant characteristics of BC cells through enhancing ATF3-MMP13 interaction by inhibiting NF1. miR-217 repressed sensitivity against anti-cancer drugs by inducing autophagy of BC cells through the NF1/HSF1/ATG7 axis. Also, miR-217 could inhibit NF1 to facilitate tumorigenic ability of BC cells in vivo. Our study emphasized that miR-217 could potentially inhibit NF1 expression to activate the c-Jun, thus enhancing the expression and interaction of ATF3/MMP13 and promoting the malignant features of BC cells. Furthermore, miR-217 conferred chemoresistance on BC by enhancing BC cell autophagy, which was achieved by limiting NF1 expression to induce the HSF1/ATG7 pathway.

The lncRNA THOR interacts with and stabilizes hnRNPD to promote cell proliferation and metastasis in breast cancer.

Emerging evidence shows that the lncRNA THOR is deeply involved in the development of various cancers. However, the effects and underlying molecular mechanisms of THOR in breast cancer (BRCA) initiation and progression have not been fully elucidated. Here we show that THOR is critical for BRCA tumorigenesis by interacting with hnRNPD to regulate downstream signaling pathways. THOR expression was significantly higher in BRCA tissues than in normal tissues, and THOR upregulation was associated with a poor prognosis in BRCA patients. Functionally, THOR knockdown impaired cell proliferation, migration and invasion in BRCA cells in vitro and inhibited tumorigenesis and metastasis in a tumor xenograft model and THOR-deficient MMTV-PyMT model in vivo. Mechanistically, THOR bound to the hnRNPD protein and increased hnRNPD protein levels by maintaining hnRNPD protein stability through inhibition of the proteasome-dependent degradation pathway. The increased hnRNPD protein levels led to stabilization of its target mRNAs, including pyruvate dehydrogenase kinase 1 (PDK1), further activating downstream PI3K-AKT and MAPK signaling pathways to regulate BRCA cell proliferation and metastasis. Together, our findings indicate that THOR is a promising prognostic predictor for BRCA patients and that the THOR-hnRNPD-PDK1-MAPK/PI3K-AKT axis might be a potential therapeutic target for BRCA treatment.

Reduced Expression of KRT17 Predicts Poor Prognosis in HER2high Breast Cancer.

Breast cancer (BC) is one of the most common types of malignancies in women and greatly threatens female health. KRT17 is a member of the keratin (KRT) protein family that is abundant in the outer layer of the skin, where it protects epithelial cells from damage. Although KRT17 has been studied in many types of cancer, the expression of KRT17 in specific subtypes of BC remains to be determined. In our study, we explored the expression and prognostic implications of KRT17 in BC patients using mRNA transcriptome data and clinical BC data from The Cancer Genome Atlas (TCGA). Receiver operating characteristic (ROC) curves and the chi-square test were used to assess the diagnostic value of KRT17 expression. Quantitative real-time PCR (qRT−PCR) analysis of BC cells and tissues and immunohistochemistry (IHC) analysis of clinical tissues were used for external validation. Furthermore, the relationship between KRT17 and immune function was studied by using the CIBERSORT algorithm to predict the proportions of tumor-infiltrating immune cells (TIICs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the potential mechanisms by which KRT17 expression influences patient survival. We found that KRT17 expression was significantly lower in BC tissues than in normal tissues, especially in the luminal-A, luminal-B and human epidermal growth factor receptor-2 (HER2)+ subtypes of BC. ROC analysis revealed that KRT17 expression had moderate diagnostic value. Interestingly, decreased expression of KRT17 was significantly correlated with poor prognosis in BC patients, especially in HER2high and ERhigh patients. This trend was also verified by tissue microarray (TMA) analysis. KRT17 was found to be involved in some antitumor immune pathways, especially the IL-17 signaling pathway, and associated with multiple immune cells, such as natural killer (NK) and CD4+ T cells. In conclusion, high expression of KRT17 predicted favorable prognosis in BC patients with higher HER2 expression. This result may indicate that KRT17 plays a different role depending on the level of HER2 expression and could serve as a promising and sensitive biomarker for the diagnosis and prognostication of HER2high BC.

Expression and prognosis analysis of mitochondrial ribosomal protein family in breast cancer

Breast cancer (BC) is characterized by high morbidity. Mitochondrial ribosomal protein (MRP) family participates in mitochondrial energy metabolism, underlying BC progression. This study aims to analyze the expression and prognosis effect of the MRP genes in BC patients. GEPIA2, UALCAN, cBioPortal, and MethSurv were used to demonstrate the differential expression, genomic alteration profiles, and DNA methylation of the MRP gene family in BC. Functional enrichment analysis and protein–protein interaction network construction were performed to understand the biological function. Based on 1056 TCGA samples with the transcriptional level of MRPs, Kaplan–Meier curves, Cox, and LASSO regression were applied to explore their prognostic effects. 12 MRPs were upregulated in BC, which were associated with gene amplification and DNA methylation. MRP genetic alteration occurred in 42% of BC patients, and amplification was the most frequent variation. Functioning in its entirety, the MRP family was involved in mitochondrial translational termination, elongation, translation, and poly(A) RNA binding. High expression of MRPL1, MRPL13, MRPS6, MRPS18C, and MRPS35, as well as low levels of MRPL16, and MRPL40 significantly indicated poor prognosis in BC patients. Thus, a novel MRP-based prognostic nomogram was established and verified with favorable discrimination and calibration. We not only provided a thorough expression and prognosis analysis of the MRP family in BC patients but also constructed an MRP-based prognostic nomogram. It was suggested that MRPs acted as biomarkers in individualized risk prediction and may serve as potential therapeutic targets in BC patients.

Abstract 3272: Attenuation of HER3-EGFR signaling augments antitumor activity of panobinostat in triple negative breast cancer

Abstract Introduction: Histone deacetylases (HDACs) are dysregulated in human cancers, making them a valuable therapeutic target. The pan-HDAC inhibitor (HDACi) panobinostat is an approved anticancer drug for patients with multiple myeloma. It has been shown that triple negative breast cancer (TNBC), as compared to other breast cancer (BC) subtypes, is more sensitive to panobinostat. Despite the positive data observed in experimental models, to date this HDACi (panobinostat) has not yielded promising results in clinical trials for most solid tumors, including BC. Thus, a better understanding of the molecular mechanisms underlying the action of panobinostat is required to design effective therapeutic strategies against TNBC. Methods: Cell growth MTS assays and LIVE/DEAD cell viability assays were used to determine cell viability. Co-immunoprecipitation (Co-IP) and Western blot were performed to assess the expression, interaction and activation of proteins. Quantitative real-time PCR (qRT-PCR) assays were carried out to measure the expression levels of mRNAs. Lentiviral vectors containing cDNA or specific shRNAs were used to overexpress or knockdown gene expression. Tumor xenograft models via subcutaneous inoculation of MDA-MB-231 cells into nude mice were established to test the in vivo antitumor activity of panobinostat alone or its combination with the EGFR inhibitor gefitinib. Results: Elevated expression of HDAC1/2/3 was observed in BC and significantly associated with poor prognosis in BC patients. In general, all TNBC cells were sensitive to panobinostat-induced growth inhibition and apoptosis. However, in the TNBC cells with HER3-low/undetectable expression, treatment with panobinostat induced upregulation of HER3, and increased the levels of phosphorylated HER3 (p-HER3) and Akt (p-Akt). Specific knockdown of HER3 via shRNAs or inhibition of HER3 by our monoclonal antibody (4A7) sensitized TNBC cells to panobinostat-induced growth inhibition and apoptosis. Further studies revealed an enhanced interaction between HER3 and EGFR due to panobinostat-induced upregulation of HER3. Combinations of panobinostat and the EGFR inhibitor gefitinib exhibited a synergistic effect inhibiting cell growth and promoting apoptosis in TNBC cells. Moreover, in the tumor xenograft models established with MDA-MB-231 cells, panobinostat in combination with gefitinib significantly inhibited tumor growth and induced apoptosis in vivo. Conclusion: While panobinostat exhibits potent anti-proliferative/anti-survival activity in TNBC cells, upregulating HER3 may be an adaptive response compromising the therapeutic potential of panobinostat. Simultaneous targeting of HER3 and its oncogenic dimerization partner, such as EGFR holds promise to combat the compensatory signaling-initiated by HER3. This new therapeutic strategy potentially improves the outcomes of TNBC patients. Citation Format: Hui Lyu, Sanbao Ruan, Congcong Tan, Bolin Liu. Attenuation of HER3-EGFR signaling augments antitumor activity of panobinostat in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3272.

A Signature of Three Apoptosis-Related Genes Predicts Overall Survival in Breast Cancer.

BackgroundThe commonest malignancy in women is known as breast cancer (BC). Numerous studies demonstrated that apoptosis appears to be critical to the management and clinical outcome of BC patients. The purpose of this study is to explore the potential connection between apoptosis and BC and establish the apoptosis-associated gene signature in BC.MethodsThe data of BC patient transcripts and related clinical information comes from the Cancer Genome Atlas Database (TCGA), and the genes related to apoptosis come from the Molecular Characterization Database (MSigDB). We identified the abnormally expressed apoptosis-related genes in BC samples. The optimal apoptosis-related genes screened by Cox regression analysis were designed to construct a prognostic model for predicting BC patients. Using the Nom Chart to Predict 1-Year, 3-Year, and 5-Year overall survival for BC patients. The gene signature-related functional pathways were explored by gene set enrichment analysis (GSEA).ResultsThree genes [alpha subunit of the interleukin 3 receptor (IL3RA), apoptosis-inducing factor mitochondrial-associated 1 (AIFM1), and phosphatidylinositol-3 kinase catalytic alpha (PIK3CA)] correlated with apoptosis were shown to be strongly linked to the overall survival of BC. Survival analysis shows that the risk score is directly proportional to the poor prognosis of BC patients. Risk assessment based on three genetic characteristics (age, pathological stage N, and pathological stage M) can independently predict the prognosis of patients with BC. The Nom chart is most suitable for assessing the long-term survival rate of BC patients. The results of GSEA demonstrated that numerous cell cycle-related pathways were abundant in the high-risk group.ConclusionWe constructed an apoptosis-associated gene signature in BC, which had a potential clinical application prospect for BC patients.

Overexpression of lncRNA SLC16A1-AS1 Suppresses the Growth and Metastasis of Breast Cancer via the miR-552-5p/WIF1 Signaling Pathway

BackgroundBreast cancer (BC) is the most common cancer and the fifth leading cause of cancer mortality with 685,000 deaths worldwide in 2020. Long non-coding RNAs (lncRNAs) are critical in BC carcinogenesis and progression. However, the functional roles and mechanisms of SLC16A1-AS1 in BC are unknown.MethodsThe expression profile of SLC16A1-AS1 in BC patients was investigated using data from The Cancer Genome Atlas (TCGA) database and checked in 80 BC patients, followed by analyzing the prognostic value of SLC16A1-AS1 in the 80 BC patients. The biological functions of SLC16A1-AS1 were further examined in vivo and in vitro after overexpression of SLC16A1-AS1 in BC cells. Possible binding sites between SLC16A1-AS1 and miR-552-5p were predicted by miRDB and those between miR-552-5p and Wnt inhibitory factor-1 (WIF1) were predicted by miRanda, which were confirmed using dual-luciferase reporter assay with mutation. Spearman correlation assay was applied to evaluate the association between genes. Rescue experiments were further applied to investigate the molecular mechanisms involved.ResultsLower SLC16A1-AS1 expression in BC tissues was related to poor prognosis of BC patients. Upregulation of SLC16A1-AS1 suppressed BC cell viability, colony formation, invasion, and migration in vitro and growth in vivo via sponging miR-552-5p to release WIF1.ConclusionSLC16A1-AS1 is a tumor suppressor in BC, and lower SLC16A1-AS1 expression is an indicator of poor prognosis in BC patients. SLC16A1-AS1 inhibits BC carcinogenesis and progression via the SLC16A1-AS1/miR-552-5p/WIF1 pathway. SLC16A1-AS1 represents a novel diagnostic, therapeutic, and prognostic target for BC management.

Circ-TFF1 Promotes Breast Cancer Progression Through the miR-129-2-3p/IRAK1 Axis.

Breast cancer (BC) is a common malignant tumor, and circular RNA-trefoil factor 1 (circ-TFF1; hsa_circ_0061825) has been found to be highly expressed in BC tissues and cells and is associated with the poor prognosis of BC patients. However, the interaction between circ-TFF1 and microRNA in BC has not been studied. Quantitative real-time PCR was used to detect the expression of circ-TFF1, miR-129-2-3p, and interleukin (IL)-1 receptor-associated kinase 1 (IRAK1). Through the detection of cell proliferation, migration, invasion, tube formation, and apoptosis, cell function was assessed. The expression levels of angiogenesis-related proteins were detected by western blot. The interaction between miR-129-2-3p and circ-TFF1 or IRAK1 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. Xenotransplantation experiments were used to confirm the function of circ-TFF1 in vivo. Circ-TFF1 and IRAK1 were significantly high expressed in BC tissues and cells. Silencing of circ-TFF1 reduced the proliferation, migration, invasion and tube formation, while increased the apoptosis of MDA-MB-361 and SK-Br-3 cells. MiR-129-2-3p was a target of circ-TFF1. Silencing of circ-TFF1 inhibited the malignant behavior of BC cells by releasing miR-129-2-3p. In addition, IRAK1 was a target of miR-129-2-3p. Overexpression of IRAK1 partially restored the inhibitory effect of miR-129-2-3p on cell progression. Animal experiments confirmed the anti-tumor effect of circ-TFF1 knockdown in vivo. Circ-TFF1 regulated the expression of IRAK1 by sponging miR-129-2-3p, thereby, promoting the development of BC. These data provided a novel targeted therapy for BC.

Ultrasound targeted microbubble destruction-mediated SOCS3 attenuates biological characteristics and epithelial-mesenchymal transition (EMT) of breast cancer stem cells

ABSTRACT SOCS3 is low-expressed in breast cancer and may be a potential target. Ultrasound targeted microbubble destruction (UTMD) improved the efficiency of gene transfection. We explored the effects of UTMD-mediated transfection of SOCS3 on the biological characteristics and epithelial-mesenchymal transition (EMT) of breast cancer stem cells (BCSCs). The expression of SOCS3 in breast cancer (BC) and its association with prognosis were evaluated by GEPIA and The Cancer Genome Atlas (TCGA) websites. BCSCs were sorted by flow cytometry and immunomagnetic bead method, followed by sphere formation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and xenograft assays to test their effects in vitro and in vivo. The levels of SOCS3, EMT- and STAT3 pathway-related genes were determined by RT-qPCR and Western blot, respectively. The effects of liposome and UTMD on BCSCs and mice were compared by the gain-of-function experiments. Low expression of SOCS3 was associated with poor prognosis of BC patients, and found in BC and BCSCs. BCSCs were successfully sorted, with high viability and tumorigenicity. UTMD increased the transfection rate of SOCS3. Moreover, UTMD- and liposome-mediated SOCS3 reduced cell viability, proliferation, migration and invasion, blocked cell cycle, inhibited sphere formation in BCSCs, and retarded tumor growth in mice. Mechanistically, overexpressed SOCS3 inhibited the expressions of EMT-related genes and the activation of STAT3 pathway in BCSCs and mice. The regulatory effects of UTMD-mediated SOCS3 on the above-mentioned biological characteristics were better than liposome-mediated SOCS3. UTMD-mediated SOCS3 has a better therapeutic effect in BC, providing new experimental evidence for the treatment of BC.

Potentials of CCL21 and CBS as Therapeutic Approaches for Breast Cancer

Objective: The present research set out to ascertain the roles of CC chemokine ligand 21 (CCL21) and cystathionine beta-synthase (CBS) in breast cancer (BC) cell biological behaviors and the relationship of CCL21 and CBS expression with the clinicopathological features of patients with BC. Methods: Immunohistochemistry of CCL21 or CBS was performed in 18 intraductal cancer tissues, 124 invasive BC tissues, 50 paraneoplastic tissues, 50 lobular hyperplasia tissues, and 30 normal breast tissues. For cell experiments, two human BC cell lines (MDA-MB-231 and MCF-7) and a human breast epithelial cell line (MCF-10A) were utilized to detect the expression of CCL21 and CBS. After loss- and gain-of-function assays for CCL21 or CBS, the expression of CBS and CCL21 was measured by quantitative real-time polymerase chain reaction and western blot. Additionally, BC cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-ethynyl-2′-deoxyuridine staining, and BC cell migration was determined by scratch test and Transwell assay. Results: In the clinical data, the positive rate of CCL21 or CBS was significantly higher in invasive BC tissues than in intraductal BC tissues, lobular hyperplasia tissues, paraneoplastic tissues, and normal breast tissues (p < 0.05 or p < 0.01). CBS or CCL21 expression shared close association with the clinicopathological characteristics and the poor prognosis of BC patients. In cell experiments, overexpression of CCL21 or CBS enhanced the proliferative and migratory abilities of BC cells. Conclusion: CCL21 and CBS promoted BC cell migration and proliferation. CCL21 or CBS expression was strongly related to the poor prognosis of BC patients.

The expression and prognostic value of minichromosome maintenance markers in human breast cancer: a comprehensive analysis

Objective: Breast cancer (BC) is one of the most health-threatening neoplasms for women worldwide. Despite advances in detection and treatment strategies over the past few decades, the current biomarkers of BC are less than satisfactory for effective prognosis and individualized treatment. This study aimed to investigate the new biomarkers to meet this urgent demand. Methods: The current study investigated the transcriptional levels of minichromosome maintenance genes (MCMs) in BC patients from the Oncomine, UALCAN database, and Gene Expression Profiling Interactive Analysis (GEPIA); protein expression levels of MCM proteins in BC patients were derived from the Human Protein Atlas (HPA) database. Further, survival analysis was evaluated with Kaplan-Meier Plotter. BC genome atlas data were obtained from cBioPortal databases. Gene regulatory network analysis was performed using the STRING online tool, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using DAVID. Results: Based on multiple database analysis, mRNA and protein levels of MCM2, MCM4 and MCM10 were much higher in BC patient, and survival analysis showed that high transcription levels of most MCMs were found to be associated with poor prognosis for BC patients; moreover, the MCMs genetic alterations, especially of MCM2, MCM4 and MCM10, were found in 45% of BC patients. In addition, dysregulation of MCMs was considered to possibly affect DNA damage/repair, cell cycle dysregulation and chromosome instability. Conclusions: In summary, this study indicated that MCM2, MCM4, and MCM10 are potential prognostic markers and therapeutic targets for BC.

Hypoxia-inducible CircPFKFB4 Promotes Breast Cancer Progression by Facilitating the CRL4DDB2 E3 Ubiquitin Ligase-mediated p27 Degradation

Hypoxic microenvironment and circular RNAs (circRNAs) have shown critical implications in breast cancer (BC) progression. However, the specific functions and underlying mechanisms of circRNAs in BC under hypoxia remain largely unknown. We first screened for differentially expressed circRNAs in normoxic and hypoxic MCF-7 cells using circRNA microarray. A novel hypoxia-induced circRNA, circPFKFB4, was identified. Clinical investigation showed that circPFKFB4 was highly expressed in BC tissues and cell lines, and its overexpression was positively correlated with the advanced clinical stage and poor prognosis of BC patients. Functionally, circPFKFB4 promoted the proliferation of BC cells both in vitro and in vivo. Mechanistically, HIF1α bound to hypoxia response elements in the promoter region of the PFKFB4 gene to facilitate the biogenesis of circPFKFB4 under hypoxia. Hypoxia-induced circPFKFB4 directly bound to both DDB1 and DDB2 and promoted the CRL4DDB2 E3 ubiquitin ligase assembly, resulting in p27 ubiquitination and BC progression under hypoxia. Our findings revealed a novel interaction between circPFKFB4 and the CRL4DDB2 E3 ubiquitin ligase, suggesting that circPFKFB4 might serve as a promising biomarker and therapeutic target for BC.

Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer.

Background: Metastasis is the leading cause of death in patients with breast cancer (BC). Primary tumors create a premetastatic niche (PMN) in secondary organs for subsequent metastases. Cancer-associated fibroblasts (CAFs) are a predominant stromal component in the tumor microenvironment and serve as a major contributor to tumor metastasis. However, the function and mechanism of primary CAFs in the premetastatic niche of secondary organs remain unclear in BC. Methods: We investigated the expression profiles of lncRNAs in pairs of CAFs and NFs derived from breast tumor tissues using lncRNA microarray. The expression levels of lncSNHG5, ZNF281, IGF2BP2, CCL2 and CCL5 were assessed by qRT-PCR; the protein levels of related genes (e.g., ZNF281, IGF2BP2, CCL2, and CCL5) were analyzed using western blotting and/or ELISA in primary and immortalized CAFs and clinical samples. Tubule formation and three-dimensional sprouting assays and tissue fluorescence staining were conducted to investigate angiogenesis. In vitro permeability assays, trans-endothelial invasion assays, in vivo permeability assays and tissue fluorescence staining were conducted to examine vascular permeability. The regulatory mechanism of lncSNHG5 was investigated by RNA sequencing, fluorescent in situ hybridization, cellular fractionation assay, mass spectrometry, RNA pull-down, RNA immunoprecipitation, gene-specific m6A assay, chromatin immunoprecipitation, dual luciferase reporter assay and actinomycin D treatment in CAFs and NFs. Results: LncSNHG5 was highly expressed in breast CAFs and played an essential role in premetastatic niche formation by promoting angiogenesis and vascular leakiness through regulation of ZNF281 in CAFs. lncSNHG5 enhanced ZNF281 mRNA stability by binding with the m6A reader IGF2BP2. Enhanced ZNF281 transcriptionally regulated CCL2 and CCL5 expression to activate P38 MAPK signaling in endothelial cells. High CCL2 and CCL5 expression was associated with tumor metastasis and poor prognosis in BC patients. The inhibitors RS102895, marasviroc and cenicriviroc inhibited angiogenesis and vascular permeability in the PMN by blocking the binding of CCL2/CCR2 and CCL5/CCR5. The lncSNHG5-ZNF281-CCL2/CCL5 signaling axis plays an essential role in inducing premetastatic niche formation to promote BC metastasis. Conclusions: Our work demonstrates that lncSNHG5 and its downstream signaling ZNF281-CCL2/CCL5 in CAFs play a crucial role in premetastatic niche formation in breast cancer and may serve as potential targets for the diagnosis and treatment of BC metastasis.

Assessment of the prognostic role of body mass index on breast cancer survivors: A Moroccan center experience

Positive association between elevated body mass index (BMI) and reduced survival in breast cancer (BC) women was demonstrated in previous meta-analyses of published data. Meanwhile, recent studies have reported that low BMI was associated with BC recurrence and overall mortality, which is paradoxical. The aim of our study was to evaluate the impact of BMI on mortality risk in a population of BC survivors. This retrospective study included 2284 female BC survivors recruited from the registry of the cardio-oncology unit of Casablanca between 2014 and 2021. BMI defined by the WHO criteria as follow: underweight (UW; BMI < 18.5 kg/m 2 ), normal weight (NW; BMI = 18.5–24.9 kg/m 2 ) and overweight or obese (OW; BMI ≥ 25 kg/m 2 ). We performed to evaluate the association between low BMI and clinical outcome in BC patients. The clinicopathological characteristics and clinical outcomes of patients after BC diagnosis were analyzed. In our study, 9.2% patients were UW and 23.9% were OW. OW group was associated with older age, larger size tumors, and higher cardiotoxicity ( P = 0.032, 0.025, P < 0.001, respectively). The overall survival (OS) decreased in OW patients ( P = 0.014), and both OW and obesity were independent predictors for increased risks of BC relapse and death ( P = 0.028). On the other hand, UW was more prominent in young women ( P = 0.018) and no significant association was found between BC recurrence rate and the UW group ( P = 0.082 and 0.056, respectively). However, multivariate regression analysis found that low BMI was an independent OS prognostic factor in young patients [HR: 1.72 (95% CI: 1.18–2.32), P = 0.029]. Our results demonstrate the prognostic role of BMI on BC survivors that might depend on patients’ age and clinical stage. Both overweight and underweight might be independently associated with poorer prognosis in BC patients. Efforts should be made to maintain BC patients in normal weight in order to improve survival.

Soyasaponin Ag inhibits triple-negative breast cancer progression via targeting the DUSP6/MAPK signaling.

Soyasaponins are triterpenoid glycosides discovered in soybean and have anti-cancer properties. Soyasaponin A was reported to repress estrogen-insensitive breast cancer cell proliferation. This study intends to explore the role of one isomer of soyasaponin A, i.e. soyasaponin Ag (Ssa Ag), in triple-negative breast cancer (TNBC) development. Bioinformatic databases were used to predict DUSP6 expression in breast cancer (BC) as well as the correlation between the expression of DUSP6 (or MAPK1, MAPK14) with the prognosis of patients with BC. The expression of DUSP6/MAPK signaling-related genes (DUSP6, MAPK1, and MAPK14) in TNBC cell lines was assessed via Western blot analysis and RT-qPCR. Levels of cell apoptosis proteins (Bax and Bcl-2) in TNBC cells were assessed via Western blot analysis. CCK-8 assay, colony formation assay, and flow cytometry analysis were conducted for the measurement of TNBC cell growth and apoptosis. In vivo xenograft assay was employed for investigating the biological influence of Ssa Ag on tumor growth. The poor prognosis of BC patients was linked to the aberrant expression of DUSP6/MAPK pathway genes. Low expression of DUSP6 or high expression of MAPK1 (or MAPK14) was correlated to poor prognosis. DUSP6 was downregulated while MAPK1 and MAPK14 were upregulated in TNBC cells versus normal cells. Ssa Ag upregulated DUSP6 expression while downregulated MAPK1 and MAPK14 expression, inhibiting the MAPK signaling pathway. Additionally, Ssa Ag promoted in vitro TNBC cell apoptosis and restrained cell growth, and repressed in vivo tumor growth. Ssa Ag inhibited TNBC progression via upregulating DUSP6 and inactivating the MAPK signaling pathway.

Drug Delivery of Natural Products Through Nanocarriers for Effective Breast Cancer Therapy: A Comprehensive Review of Literature.

Despite recent advances in the diagnosis and treatment of breast cancer (BC), it remains a global health issue affecting millions of women annually. Poor prognosis in BC patients is often linked to drug resistance as well as the lack of effective therapeutic options for metastatic and triple-negative BC. In response to these unmet needs, extensive research efforts have been devoted to exploring the anti-BC potentials of natural products owing to their multi-target mechanisms of action and good safety profiles. Various medicinal plant extracts/essential oils and natural bioactive compounds have demonstrated anti-cancer activities in preclinical BC models. Despite the promising preclinical results, however, the clinical translation of natural products has often been hindered by their poor stability, aqueous solubility and bioavailability. There have been attempts to overcome these limitations, particularly via the use of nano-based drug delivery systems (NDDSs). This review highlights the tumour targeting mechanisms of NDDSs, the advantages and disadvantages of the major classes of NDDSs and their current clinical status in BC treatment. Besides, it also discusses the proposed anti-BC mechanisms and nanoformulations of nine medicinal plants’ extracts/essential oils and nine natural bioactive compounds; selected via the screening of various scientific databases, including PubMed, Scopus and Google Scholar, based on the following keywords: “Natural Product AND Nanoparticle AND Breast Cancer”. Overall, these nanoformulations exhibit improved anti-cancer efficacy against preclinical BC models, with some demonstrating biocompatibility with normal cell lines and mouse models. Further clinical studies are, however, warranted to ascertain their efficacy and biocompatibility in humans.

High expression of eIF4E is associated with tumor macrophage infiltration and leads to poor prognosis in breast cancer

BackgroundThe expression and activation of eukaryotic translation initiation factor 4E (eIF4E) is associated with cell transformation and tumor initiation, but the functional role and the mechanism whereby it drives immune cell infiltration in breast cancer (BRCA) remain uncertain.MethodsOncomine, Timer and UALCAN were used to analyze the expression of eIF4E in various cancers. PrognoScan, Kaplan–Meier plotter, and GEPIA were utilized to analyze the prognostic value of eIF4E in select cancers. In vitro cell experiments were used to verify the role of eIF4E in promoting the progression of BRCA. ImmuCellAI and TIMER database were used to explore the relationship between eIF4E and tumor infiltrating immune cells. The expression of a macrophage marker (CD68+) and an M2-type marker (CD163+) was evaluated using immunohistochemistry in 50 invasive BRCA samples on tissue microarrays. The Human Protein Atlas (HPA) database was used to show the expression of eIF4E and related immune markers. LinkedOmics and NetworkAnalyst were used to build the signaling network.ResultsThrough multiple dataset mining, we found that the expression of eIF4E in BRCA was higher than that in normal tissues, and patients with increased eIF4E expression had poorer survival and a higher cumulative recurrence rate in BRCA. At the cellular level, BRCA cell migration and invasion were significantly inhibited after eIF4E expression was inhibited by siRNA. Immune infiltration analysis showed that the eIF4E expression level was significantly associated with the tumor purity and immune infiltration levels of different immune cells in BRCA. The results from immunohistochemical (IHC) staining further proved that the expression of CD68+ and CD163+ were significantly increased and correlated with poor prognosis in BRCA patients (P < 0.05). Finally, interaction network and functional enrichment analysis revealed that eIF4E was mainly involved in tumor-related pathways, including the cell adhesion molecule pathway and the JAK-STAT signaling pathway.ConclusionsOur study has demonstrated that eIF4E expression has prognostic value for BRCA patients. eIF4E may act as an essential regulator of tumor macrophage infiltration and may participate in macrophage M2 polarization.

MiR-466 as a poor prognostic predictor suppresses cell proliferation and EMT in breast cancer cells by targeting PSMA7.

MiR-466 has been reported to exert a tumor-suppressive role in several cancers, including colorectal cancer and osteosarcoma, but its clinical significance and functional mechanisms in breast cancer (BC) pathogenesis still remain elusive. The expression of miR-466 was determined using reverse transcription quantitative PCR. The clinical significance of miR-466 in BC patients was assessed by Chi-square test, Kaplan-Meier method and Cox regression analyses. Functional experiments, including CCK-8 and transwell assays, were performed to analyze cell proliferation, migration and invasion ability. The association between miR-466 and proteasome subunit α7 (PSMA7) was confirmed by Luciferase reporter assay. Here, we first observed that the expression of miR-466 was significantly downregulated in BC tissues and cell lines. The decreased miR-466 expression was significantly associated with tumor size (p = 0.003), lymph node metastasis (p = 0.008), TNM stage (p = 0.032) and poor survival rate. In addition, miR-466 was identified as an independent prognostic factor for BC patients. We further found that the overexpression of miR-466 significantly inhibited cell proliferation, migration and invasion. Mechanistically, PSMA7 was a potential target gene of miR-466 and negatively regulated miR-466 in BC cells. Oncomine database and Kaplan-Meier overall survival analysis indicated that upregulation of PSMA7 was associated with poor prognosis of BC patients. The rescue experiments demonstrated that PSMA7 overexpression reversed the effects of miR-466 on cell proliferation, migration, invasion and EMT transcription factors (E-cadherin, N-cadherin, and vimentin). Collectively, these results suggest that the miR-466/PSMA7 axis might have potential as a therapeutic target for BC treatment.

AC016405.3 functions as an oncogenic long non-coding RNA by regulating ERBB3 via sponging miR-22-3p in breast cancer.

BackgroundIncreasing studies reported that long non‐coding RNAs are involved in regulating breast cancer (BRCA) progression. However, the specific roles and mechanisms of lncRNAs in BRCA remain largely unknown. Here, we sought to explore the functions and mechanisms of AC016405.3 in BRCA progression.MethodsBioinformatic analysis for AC016405.3, miR‐22‐3p, and ERBB3 were performed on starBase. The expressions of AC016405.3, miR‐22‐3p, and ERBB3 were examined by RT‐qPCR. The functions of AC016405.3 on the proliferation, migration, and invasion of cells were evaluated by conducting CCK‐8, colony formation, wound‐healing, and Transwell assays. The subcellular distribution of AC016405.3 in BRCA cells was identified by performing fluorescence in situ hybridization (FISH) and subcellular fractionation techniques. Dual‐luciferase assay was applied to validate the interactions of miR‐22‐3p with AC016405.3 or ERBB3. The interaction between ERBB3 and miR‐22‐3p was also tested by Anti‐Ago2 RNA immunoprecipitation (RIP) assay.ResultsThe results showed that AC016405.3 is highly expressed in BRCA tissues as well as cells and positively correlated with poor prognosis in BRCA patients. Silencing AC016405.3 obviously repressed the malignant behaviors of BRCA cells. Mechanistically, AC016405.3 functioned as a competing endogenous RNA (ceRNA) for miR‐22‐3p in the cytoplasm and sponged miR‐22‐3p to release its suppression of ERBB3. Rescue experiments revealed that the suppression role induced by AC016405.3 depletion on malignant behaviors of BRCA cells could be obviously counter by inhibiting miR‐22‐3p or overexpressing ERBB3.ConclusionAC016405.3 promotes BRCA progression by the derepression of ERBB3 via sponging miR‐22‐3p, which may represent a potential target for BRCA treatment.

Antibiotics modulate neoadjuvant therapy efficiency in patients with breast cancer: a pilot analysis

Mounting evidence suggests that microbiota dysbiosis caused by antibiotic administration is a risk factor for cancer, but few research reports focus on the relationships between antibiotics and chemotherapy efficiency. We evaluated the influence of antibiotic administration on neoadjuvant therapy efficacy in patients with breast cancer (BC) in the present study. BC patients were stratified into two groups: antibiotic-treated and control based on antibiotic administration within 30 days after neoadjuvant therapy initiation. Disease-free survival (DFS) and overall survival (OS) were assessed using the Kaplan–Meier method, and the Cox proportional hazards model was used for multivariate analyses. The pathologic complete response rate of the control group was significantly higher than that of the antibiotic-treated group (29.09% vs. 10.20%, p = 0.017). Further univariate analysis with Kaplan–Meier calculations demonstrated that antibiotic administration was strongly linked with both reduced DFS (p = 0.04) at significant statistical levels and OS (p = 0.088) at borderline statistical levels. Antibiotic administration was identified as a significant independent prognostic factor for DFS [hazard ratio (HR) 3.026, 95%, confidence interval (CI) 1.314–6.969, p = 0.009] and OS (HR 2.836, 95% CI 1.016–7.858, p = 0.047) by Cox proportional hazards model analysis. Antibiotics that initiated reduced efficiency of chemotherapy were more noticeable in the HER2-positive subgroup for both DFS (HR 5.51, 95% CI 1.77–17.2, p = 0.003) and OS (HR 7.0395% CI 1.94–25.53, p = 0.003), as well as in the T3-4 subgroup for both DFS (HR 20.36, 95% CI 2.41–172.07, p = 0.006) and OS (HR 13.45, 95% CI 1.39–130.08, p = 0.025) by stratified analysis. Antibiotic administration might be associated with reduced efficacy of neoadjuvant therapy and poor prognosis in BC patients. As a preliminary study, our research made preparations for further understanding and large-scale analyses of the impact of antibiotics on the efficacy of neoadjuvant therapy.