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Abstract Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.

Background: Accumulating evidence indicates that PSAT1 not only reprogrammed metabolic function but also exhibits “moonlighting” functions in promoting tumor malignancy. However, the underlying molecular mechanisms of PSAT1 promoting ER-negative breast cancer cell migration need further investigation. Methods: Briefly, the PSAT1 and ITGA2 expression in cells and tissues was detected using qRT-PCR, immunofluorescence staining and western blot assay. The effect of PSAT1 and ITGA2 was verified both in vitro and in vivo. RNA-seq analysis explored a series of differently expressed genes. The regulation between SP1 and ITGA2 was investigated by ChIP analysis. Results: We reported PSAT1 was highly expressed in ER-breast cancer tissues and tumor cells and positively correlated with metastasis. Moreover, RNA-seq analysis explored a series of differently expressed genes, including ITGA2, in PSAT1 overexpressed cells. Mechanistically, PSAT1 facilitated breast cancer metastasis via the p-AKT/SP1/ITGA2 axis. We further elucidated that PSAT1 promoted the entry of SP1 into the nucleus through the upregulation of p-AKT and confirmed ITGA2 is a target of SP1. In addition, enhanced cell migration was remarkably reversed by ITGA2 depletion or p-AKT inhibitor treatment. Conclusion: This study clarified the mechanism of PSAT1 in promoting ER-negative breast cancer metastasis, which may provide mechanistic clues for attenuating breast cancer metastasis.

Abstract Immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized the treatment of many types of cancer, particularly advanced-stage cancers. Nevertheless, although a subset of patients experiences dramatic and long-term disease regression in response to ICIs, most patients do not benefit from these treatments. Some may even experience cancer progression. Immune escape by tumor cells may be a key reason for this low response rate. N 6-methyladenosine (m6A) is the most common type of RNA methylation and has been recognized as a critical regulator of tumors and the immune system. Therefore, m6A modification and related regulators are promising targets for improving the efficacy of tumor immunotherapy. However, the association between m6A modification and tumor immune escape (TIE) has not been comprehensively summarized. Therefore, this review summarizes the existing knowledge regarding m6A modifications involved in TIE and their potential mechanisms of action. Moreover, we provide an overview of currently available agents targeting m6A regulators that have been tested for their elevated effects on TIE. This review establishes the association between m6A modifications and TIE and provides new insights and strategies for maximizing the efficacy of immunotherapy by specifically targeting m6A modifications involved in TIE.

BackgroundCuproptosis, a recently discovered refreshing form of cell death, is distinct from other known mechanisms. As copper participates in cell death, the induction of cancer cell death with copper ionophores may emerge as a new avenue for cancer treatment. However, the role of cuproptosis in tumor microenvironment (TME) cell infiltration remains unknown.MethodsWe systematically evaluated the cuproptosis patterns in The Cancer Genome Atlas (TCGA) database in breast cancer (BRCA) samples based on 10 cuproptosis-related genes (CRGs), and correlated these patterns with the prognosis and characteristics of TME cell infiltration. A principal component analysis algorithm was used to construct a cuproptosis score to quantify the cuproptosis pattern in individual tumors. Further, the relationships between the cuproptosis score and transcription background, clinical features, characteristics of TME cell infiltration, drug response, and efficacy of immunotherapy were assessed.ResultsTwo distinct cuproptosis patterns with distinct prognoses were identified; their TME characteristics were found to be consistent with the immune-excluded and immune-inflamed phenotypes, respectively. The cuproptosis patterns in individual patients were evaluated using the cuproptosis score based on the cuproptosis phenotype-related genes, contributing to distinguishing biological processes, clinical outcome, immune cell infiltration, genetic variation, and drug response. Univariate and multivariate Cox regression analyses verified this score as an independent prognostic predictor in BRCA. A high cuproptosis score, characterized by immune activation, suggests an inflamed tumor and immune-inflamed phenotype with poor survival and a low cuproptosis score, characterized by immune suppression, indicates a non-inflamed tumor and immune-excluded phenotype with better survival. Significant differences were observed in the IC50 between the high and low cuproptosis score groups receiving chemotherapy and targeted therapy drugs. In the two immunotherapy cohorts, patients with a higher cuproptosis score experienced considerable therapeutic advantages and clinical benefits.ConclusionsThis study is the first to elucidate the prominent role of cuproptosis in the clinical outcome and the formation of TME diversity and complexity in BRCA. Estimating cuproptosis patterns in tumors could help predict the prognosis and characteristics of TME cell infiltration and guide more effective chemotherapeutic and immunotherapeutic strategies.

Background and ObjectiveSentinel lymph node biopsy (SLNB) is used to assess the status of axillary lymph node (ALN), but it causes many adverse reactions. Considering the low rate of sentinel lymph node (SLN) metastasis in T1 breast cancer, this study aims to identify the characteristics of T1 breast cancer without SLN metastasis and to select T1 breast cancer patients who avoid SLNB through constructing a nomogram.MethodsA total of 1,619 T1 breast cancer patients with SLNB in our hospital were enrolled in this study. Through univariate and multivariate logistic regression analysis, we analyzed the tumor anatomical and clinicopathological factors and constructed the Heilongjiang Medical University (HMU) nomogram. We selected the patients exempt from SLNB by using the nomogram.ResultsIn the training cohort of 1,000 cases, the SLN metastasis rate was 23.8%. Tumor volume, swollen axillary lymph nodes, pathological types, and molecular subtypes were found to be independent predictors for SLN metastasis in multivariate regression analysis. Distance from nipple or surface and position of tumor have no effect on SLN metastasis. A regression model based on the results of the multivariate analysis was developed to predict the risk of SLN metastasis, indicating an AUC of 0.798. It showed excellent diagnostic performance (AUC = 0.773) in the validation cohort.ConclusionThe HMU nomogram for predicting SLN metastasis incorporates four variables, including tumor volume, swollen axillary lymph nodes, pathological types, and molecular subtypes. The SLN metastasis rates of intraductal carcinoma and HER2 enriched are 2.05% and 6.67%. These patients could be included in trials investigating the SLNB exemption.

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Breast cancer (BRCA) is one of the leading causes of death among women worldwide, and drug resistance often leads to a poor prognosis. Necroptosis is a type of programmed cell death (PCD) and exhibits regulatory effects on tumor progression, but few studies have focused on the relationships between necroptosis-associated lncRNAs and BRCA. In this study, we established a signature basis of 7 necroptosis-related lncRNAs associated with prognosis and divided BRCA patients into high- and low-risk groups. Kaplan-Meier curves all showed an adverse prognosis for patients in the high-risk group. Cox assays confirmed that risk score was an independent prognostic factor for BRCA patients. The receiver operating characteristic (ROC) curve proved the predictive accuracy of the signature and the area under the curve (AUC) values of the risk score reached 0.722. The nomogram relatively accurately predicted the prognosis of the patients. GSEA analysis suggested that the related signaling pathways and biological processes enriched in the high- and low-risk groups may influence the tumor microenvironment (TME) of BRCA. ssGSEA showed the difference in immune cell infiltration, immune pathway activation, and immune checkpoint expression between the two risk groups, with the low-risk group more suitable for immunotherapy. According to the significant difference in IC50 between risk groups, patients can be guided for an individualized treatment plan. Overall, the authors established a prognostic signature consisting of 7 necroptosis-associated lncRNAs that can independently predict the clinical outcome of BRCA patients. The difference in the tumor immune microenvironment between the low- and high-risk populations may be the reason for the resistance to immunotherapy in some patients.

Abstract Background An increasing number of studies have shown that long noncoding RNAs (lncRNAs) play essential roles in tumor initiation and progression. LncRNAs act as tumor promoters or suppressors by targeting specific genes via epigenetic modifications and competing endogenous RNA (ceRNA) mechanisms. In this study, we explored the function and detailed mechanisms of long intergenic nonprotein coding RNA 673 (LINC00673) in breast cancer progression. Methods Quantitative real-time PCR (qRT-PCR) was used to examine the expression of LINC00673 in breast cancer tissues and in adjacent normal tissues. Gain-of-function and loss-of function experiments were conducted to investigate the biological functions of LINC00673 in vitro and in vivo. We also explored the potential role of LINC00673 as a therapeutic target using antisense oligonucleotide (ASO) in vivo. RNA sequencing (RNA-seq), dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP) assay, and rescue experiments were performed to uncover the detailed mechanism of LINC00673 in promoting breast cancer progression. Results In the present study, LINC00673 displayed a trend of remarkably increased expression in breast cancer tissues and was associated with poor prognosis in breast cancer patients. Importantly, LINC00673 depletion inhibited breast cancer cell proliferation by inhibiting the cell cycle and increasing apoptosis. Furthermore, ASO therapy targeting LINC00673 substantially suppressed breast cancer cell proliferation in vivo. Mechanistically, LINC00673 was found to act as a ceRNA by sponging miR-515-5p to regulate MARK4 expression, thus inhibiting the Hippo signaling pathway. Finally, ChIP assay showed that the transcription factor Yin Yang 1 (YY1) could bind to the LINC00673 promoter and increase its transcription in cis. Conclusions YY1-activated LINC00673 may exert an oncogenic function by acting as a sponge for miR-515-5p to upregulate the MARK4 and then inhibit Hippo signaling pathway, and may serve as a potential therapeutic target.

Abstract Background The landscape and biological functions of tumor suppressor long noncoding RNAs in breast cancer are still unknown. Methods Data from whole transcriptome sequencing of 33 breast specimens in the Harbin Medical University Cancer Center cohort and The Cancer Genome Atlas was applied to identify and validate the landscape of tumor suppressor long noncoding RNAs, which was further validated by The Cancer Genome Atlas pancancer data including 33 cancer types and 12,839 patients. Next, the expression model, prognostic roles, potential biological functions and epigenetic regulation of tumor suppressor long noncoding RNAs were investigated and validated in the breast cancer and pancancer cohorts. Finally, EPB41L4A-AS2 was selected to validate our novel finding, and the tumor suppressive roles of EPB41L4A-AS2 in breast cancer were examined. Results We identified and validated the landscape of tumor suppressor long noncoding RNAs in breast cancer. The expression of the identified long noncoding RNAs was downregulated in cancer tissue samples compared with normal tissue samples, and these long noncoding RNAs correlated with a favorable prognosis in breast cancer patients and the patients in the pancancer cohort. Multiple carcinogenesis-associated biological functions were predicted to be regulated negatively by these long noncoding RNAs. Moreover, these long noncoding RNAs were transcriptionally regulated by epigenetic modification, including DNA methylation and histone methylation modification. Finally, EPB41L4A-AS2 inhibited breast cancer cell proliferation, migration and invasion and induced cell apoptosis in vitro. Mechanistically, EPB41L4A-AS2, acting at least in part as a tumor suppressor, upregulated tumor suppressor gene expression. Moreover, ZNF217 recruited EZH2 to the EPB41L4A-AS2 locus and suppressed the expression of EPB41L4A-AS2 by epigenetically increasing H3K27me3 enrichment. Conclusions This work enlarges the functional landscape of known long noncoding RNAs in human cancer and provides novel insights into the suppressive roles of these long noncoding RNAs.

Several studies have found that DNA methylation is associated with transcriptional regulation and affect sponge regulation of non-coding RNAs in cancer. The integration of circRNA, miRNA, DNA methylation and gene expression data to identify sponge circRNAs is important for revealing the role of DNA methylation-mediated regulation of sponge circRNAs in cancer progression. We established a DNA methylation-mediated circRNA crosstalk network by integrating gene expression, DNA methylation and non-coding RNA data of breast cancer in TCGA. Four modules (26 candidate circRNAs) were mined. Next, 10 DNA methylation-mediated sponge circRNAs (sp_circRNAs) and five sponge driver genes (sp_driver genes) in breast cancer were identified in the CMD network using a computational process. Among the identified genes, ERBB2 was associated with six sponge circRNAs, which illustrates its better sponge regulatory function. Survival analysis showed that DNA methylations of 10 sponge circRNA host genes are potential prognostic biomarkers in the TCGA dataset (p = 0.0239) and GSE78754 dataset (p = 0.0377). In addition, the DNA methylation of two sponge circRNA host genes showed a significant negative correlation with their driver gene expressions. We developed a strategy to predict sponge circRNAs by DNA methylation mediated with playing the role of regulating breast cancer sponge driver genes.