Prognostic Marker In Breast Cancer Research Articles

Current evidence on circRNAs as potential theranostic markers for detecting chemoresistance in breast cancer: a systematic review and meta‑analysis

This study assessed the value of circRNAs (circular RNAs) as prognostic markers in BC (breast cancer). We searched pertinent studies on the PubMed, Embase, and Web of Science online databases published according to PRISMA guidelines. A random-effects model for meta-analysis was used to assess the combined effect size of the HRs (hazard ratios) of the included studies. The heterogeneity test used Cochran's Q-test and I2 statistics. Thirty of the 520 trials retrieved were included in the systematic review. A total of 11 chemotherapeutic agents were used in the included studies. A total of 30 studies on 30 circRNAs were included in the systematic review. Of the 30 relevant circRNAs, 28 were upregulated and two were downregulated in breast cancer versus normal samples, and both were associated with increased drug resistance. Nine of 30 studies were used for the meta-analysis. The results of the meta-analysis showed that the groups with circRNA upregulation and circRNA downregulation showed the same prognostic risk (HR = 1.37, 95% Cl: 0.80–2.36, I2 = 63.7%). The results of subgroup analysis showed that both upregulated circRNAs (HR = 2.24, 95% Cl: 1.34–3.75, I2 = 0%) and downregulated circRNAs (HR = 0.61, 95% Cl: 0.45–0.83, I2 = 0%) were associated with poor BC prognosis. Collectively, the results of all relevant articles collected indicated that circRNAs showed good potential as possible clinical biomarkers of chemoresistance in BC patients.

TG2 as a novel breast cancer prognostic marker promotes cell proliferation and glycolysis by activating the MEK/ERK/LDH pathway

BackgroundBreast cancer (BC) is the most common malignant tumor among women worldwide. Tissue transglutaminase 2 (TG2) has been reported as a major player across several types of cancer. However, the effects of TG2 in breast cancer are less known.MethodsThe expression of TG2 in patients with BC was detected by immunochemistry staining and RT-qPCR. The correlation of TG2 expression and clinicopathological factors or overall survival (OS) was analyzed by Chi-square test, Kaplan-Meier, and Cox-regression analysis. The effects of TG2 on cell proliferation and glycolysis were investigated in vivo and in vitro by gain- and loss-of-function experiments.ResultBoth mRNA and protein levels of TG2 were overexpressed in BC tissues and cultured cells. Clinical stage (p = 0.011), molecular subtype (p<0.001) and survival status (p<0.001) were significantly correlated with TG2 expression. Specifically, TG2 expression was positively associated with the clinical stage (r = 0.193, p = 0.005) and OS (r = 0.230, p = 0.001), while negatively associated with molecular subtype (r = − 0.161, p = 0.020). Overexpressed TG2 was a prognostic factor of poor OS by Cox-regression analysis. Gain- and loss-of-function experiments indicated that cell proliferation and glycolysis were regulated by TG2 via the MEK/ERK/LDH pathway. TG2-induced activation of the MEK/ERK/LDH pathway and glycolysis were attenuated by MEK inhibitor U0126.ConclusionTG2 is overexpressed in BC, which can serve as an independent prognostic factor for OS. TG2 promotes tumor cell proliferation and increases glycolysis associated with the activation of the MEK/ERK/LHD pathway.

Serum LAPTM4B as a Potential Diagnostic and Prognostic Biomarker for Breast Cancer.

Lysosome-associated protein transmembrane-4 beta (LAPTM4B) is an integral membrane protein overexpressed in various cancers and may function as a prognostic tumor marker. The present study is aimed at understanding the clinical significance of serum LAPTM4B in breast cancer (BC). Serum LAPTM4B level was evaluated in 426 BC patients, 40 benign breast disease, and 80 healthy controls by ELISA. We used the receiver operator characteristic (ROC) curve to assess the diagnostic significance. 46 BC patients were recruited to monitor the dynamic change of serum LAPTM4B during adjuvant therapy (AT). In addition, sera from a subset of 330 patients undergoing AT, including anti-HER2 treatment, were collected to evaluate the association between LAPTM4B levels and AT efficacy. Descriptive and explorative statistical analyses were used to assess LAPTM4 B's potential as a diagnostic and prognostic marker in BC. Serum LAPTM4B level was significantly increased in BC patients than benign group and controls. It could well discriminate BC from healthy controls with diagnostic accuracy with an AUC of 0.912, a sensitivity of 85.9%, and a specificity of 83.8%. Compared with pre-AT, serum LAPTM4B concentration remarkably decreased after AT. In addition, patients in the invalid response group (PD + SD) showed higher LAPTM4B levels than the valid response group (PR + CR). Our results proposed that serum LAPTM4B had a high diagnostic and prognostic impact as a circulating biomarker in BC.

Upregulation of NUAK2: A novel prognostic marker in breast cancer.

Breast cancer is the most commonly diagnosed neoplasm in women worldwide. New molecular biomarkers and effective prognostic models are being developed. This study aimed to investigate the clinical and prognostic significance of NUAK2 expression in patients with breast cancer. The expression of NUAK 2 was examined in breast cancer cells and tissues by real-time PCR, western blotting, and immunohistochemical staining. CCK-8 and colony formation assays were performed to verify the effect of NUAK2 on the proliferation and tumor progression of breast cancer cells. A tumor formation assay in nude mice was performed to analyze the effect of NUAK2 on the tumorigenicity of breast cancer cells. The expression of NUAK2 in breast cancer tissues was higher than that in paracarcinoma and normal breast tissues. The overall survival of patients with high NUAK2 expression was significantly lower than that of patients with low NUAK2 expression. Multivariate analyses indicated that NUAK2 was an independent prognostic indicator of survival in breast cancer. In vitro experiments demonstrated that knocking down NUAK2 in breast cancer cells inhibited cell proliferation and tumor-forming ability, and overexpression of NUAK2 showed the opposite effects. NUAK2 overexpression promoted the tumorigenicity of breast cancer cells in vivo. These findings suggest that NUAK2 is involved in breast cancer development and progression. NUAK2 may be a valuable prognostic indicator in patients with breast cancer.

Association study of Bif-1 gene expression with histopathological characteristics and hormone receptors in breast cancer

BackgroundBreast cancer is a heterogeneous disease that has various clinical outcomes. Bax-interacting factor-1 (Bif-1) is a member of the endophilin B family that generates the pro-apoptotic BCL2-Associated X (BAX) protein in response to apoptotic signals. Lack of Bif-1 inhibits the intrinsic pathway of apoptosis and enhancements the risk of tumor genesis. The present study aimed to investigate the relationship between hormone receptors (ER, PR, and HER2) status and different levels of Bif-1 gene expression in breast cancer patients.MethodsBif-1 gene expression was evaluated in 50 breast cancer tumors and 50 normal breast mammary tissues using the SYBR Green real-time RT-PCR technique. Multivariate and univariate analyses were used to appraise the relationship between the prognostic significance of the Bif-1 gene using SPSS software. In this study, the Bif-1 was selected as a candidate for a molecular biomarker and its expression status in breast cancer patients with hormone receptors (ER, RR, and HER2) compared to patients without these hormone receptors.ResultsThe study showed that the relative expression of the Bif-1 gene in tissues of patients with hormone receptors in breast cancer compared to those without hormone receptors was not statistically significant. The expression levels of the Bif-1 gene in different groups were evaluated for hormone receptor status. No significant relationship was found between the Bif-1 gene expression and hormone receptors (ER, PR, and HER2) (p > 0.05).ConclusionBif-1 gene expression may be a useful prognostic marker in breast cancer.

ScHumanNet: a single-cell network analysis platform for the study of cell-type specificity of disease genes.

A major challenge in single-cell biology is identifying cell-type-specific gene functions, which may substantially improve precision medicine. Differential expression analysis of genes is a popular, yet insufficient approach, and complementary methods that associate function with cell type are required. Here, we describe scHumanNet (https://github.com/netbiolab/scHumanNet), a single-cell network analysis platform for resolving cellular heterogeneity across gene functions in humans. Based on cell-type-specific gene networks (CGNs) constructed under the guidance of the HumanNet reference interactome, scHumanNet displayed higher functional relevance to the cellular context than CGNs built by other methods on single-cell transcriptome data. Cellular deconvolution of gene signatures based on network compactness across cell types revealed breast cancer prognostic markers associated with T cells. scHumanNet could also prioritize genes associated with particular cell types using CGN centrality and identified the differential hubness of CGNs between disease and healthy conditions. We demonstrated the usefulness of scHumanNet by uncovering T-cell-specific functional effects of GITR, a prognostic gene for breast cancer, and functional defects in autism spectrum disorder genes specific for inhibitory neurons. These results suggest that scHumanNet will advance our understanding of cell-type specificity across human disease genes.

Prolylcarboxypeptidase promotes IGF1R/HER3 signaling and is a potential target to improve endocrine therapy response in estrogen receptor positive breast cancer

ABSTRACT Prolylcarboxypeptidase (PRCP) is a lysosomal serine protease that cleaves peptide substrates when the penultimate amino acid is proline. Previous studies have linked PRCP to blood-pressure and appetite control through its ability to cleave peptide substrates such as angiotensin II and α-MSH. A potential role for PRCP in cancer has to date not been widely appreciated. Endocrine therapy resistance in breast cancer is an enduring clinical problem mediated in part by aberrant receptor tyrosine kinase (RTK) signaling. We previously found PRCP overexpression promoted 4-hydroxytamoxifen (4-OHT) resistance in estrogen receptor-positive (ER+) breast cancer cells. Currently, we tested the potential association between PRCP with breast cancer patient outcome and RTK signaling, and tumor responsiveness to endocrine therapy. We found high PRCP protein levels in ER+ breast tumors associates with worse outcome and earlier recurrence in breast cancer patients, including patients treated with TAM. We found a PRCP specific inhibitor (PRCPi) enhanced the response of ER+ PDX tumors and MCF7 tumors to endoxifen, an active metabolite of TAM in mice. We found PRCP increased IGF1R/HER3 signaling and AKT activation in ER+ breast cancer cells that was blocked by PRCPi. Thus, PRCP is an adverse prognostic marker in breast cancer and a potential target to improve endocrine therapy in ER+ breast cancers.

260 (PB-084) Poster - The combination of platelet-to-lymphocyte ratios with TIL assessment as prognostic factor for patients with triple negative breast cancer

Background: Tumor infiltrating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately.

CHEMOTHERAPY INDUCED HISTOPATHOLOGICAL CHANGES IN MASTECTOMY SPECIMENS - STUDY AT A TERTIARY CARE CENTRE

Background: Pathological complete response (pCR) to Neo adjuvant chemotherapy (NACT) is a signicant prognostic marker in breast cancer, so accurate diagnosis and grading of pathological chemo response of tumour is needed for an effective planning of treatment regimen. To study the various histopathological Aims: changes in Mastectomy specimens following NACT and to evaluate the pathological response of tumour to NACT, also to compare the expression of ER, PR, and HER2 in biopsies and post NACT mastectomy specimens by Immunohistochemistry (IHC). Methods And Materials: 50 breast carcinoma cases, who was diagnosed on trucut biopsies and treated with preoperative NACT followed by mastectomy was included. In post NACT mastectomy specimens, the chemoresponse was classied according to Union for International Cancer Control (UICC) guidelines. ER, PR, and HER2/ neu receptor expression was compared between trucut biopsy specimens (pre- NACT) and resection specimens (post- NACT). Results were analysed by Chi square test and McNemar chi square test. Among 50 cases, patients presented with lump, Results: involved more on the right and in upper outer quadrant. Most common stage at presentation is stage III A. Histologically all belong to IDCC -NST histological subtype. Signicant reduction in mean tumour size by 52.7% after NACT was observed. pCR, pPR and pNR was observed in 20 %, 58 % and 22 %of the cases respectively. Most common histological change seen in post NACT is necrosis, desmoplasia, brosis, lymphocytic inammatory response. Discordance in ER expression (17.5 %), PR expression (20%) and HER2 /neu (12.5 %) before and after NACT. But these were statistically insignicant. CONCLUSIONS: Pathological evaluation of chemo response of tumour is the gold standard. The discordance rate of ER, PR and HER-2/neu expression following NACT was statistically insignicant, larger studies needed to analyse their impact in patient management.

Identifying enhancer-driven subtype-specific prognostic markers in breast cancer based on multi-omics data.

Breast cancer is a cancer of high complexity and heterogeneity, with differences in prognosis and survival among patients of different subtypes. Copy number variations (CNVs) within enhancers are crucial drivers of tumorigenesis by influencing expression of their targets. In this study, we performed an integrative approach to identify CNA-driven enhancers and their effect on expression of target genes in four breast cancer subtypes by integrating expression data, copy number data and H3K27ac data. We identified 672, 555, 531, 361 CNA-driven enhancer-gene pairs and 280, 189, 113 and 98 CNA-driven enhancer-lncRNA pairs in the Basal-like, Her2, LumA and LumB subtypes, respectively. We then reconstructed a CNV-driven enhancer-lncRNA-mRNA regulatory network in each subtype. Functional analysis showed CNA-driven enhancers play an important role in the progression of breast cancer subtypes by influencing P53 signaling pathway, PPAR signaling pathway, systemic lupus erythematosus and MAPK signaling pathway in the Basal-like, Her2, LumA and LumB subtypes, respectively. We characterized the potentially prognostic value of target genes of CNV-driven enhancer and lncRNA-mRNA pairs in the subtype-specific network. We identified MUM1 and AC016876.1 as prognostic biomarkers in LumA and Basal-like subtypes, respectively. Higher expression of MUM1 with an amplified enhancer exhibited poorer prognosis in LumA patients. Lower expression of AC016876.1 with a deleted enhancer exhibited poorer survival outcomes of Basal-like patients. We also identified enhancer-related lncRNA-mRNA pairs as prognostic biomarkers, including AC012313.2-MUM1 in the LumA, AC026471.4-PLK5 in the LumB, AC027307.2-OAZ1 in the Basal-like and AC022431.1-HCN2 in the Her2 subtypes. Finally, our results highlighted target genes of CNA-driven enhancers and enhancer-related lncRNA-mRNA pairs could act as prognostic markers and potential therapeutic targets in breast cancer subtypes.

Role of epigallocatechin-3- gallate in the regulation of known and novel microRNAs in breast carcinoma cells.

Breast cancer comprises 30% of all cancer cases among the world’s women population. MicroRNAs are small, endogenous, non-coding RNAs that regulate cell proliferating and apoptotic pathways by modulating expressions of related genes. Phytochemicals like epigallocatechin-3-gallate (EGCG) are known to have a chemotherapeutic effect on cancer often through the regulation of microRNAs. The aim is to find out the key known and novel miRNAs, which are controlled by EGCG in breast cancer cell line MDA-MB-231. Next-generation sequencing (NGS) revealed 1,258 known and 330 novel miRNAs from untreated and 83 μM EGCG (IC50 value of EGCG) treated cells. EGCG modulated 873 known and 47 novel miRNAs in the control vs. treated sample. The hypothesis of EGCG being a great modulator of miRNAs that significantly control important cancer-causing pathways has been established by analyzing with Kyoto Encyclopedia of Genes and Genomes (KEGG) and Protein Analysis Through Evolutionary Relationships (PANTHER) database. Validation of known and novel miRNA expression differences in untreated vs. treated cells was done using qPCR. From this study, a few notable miRNAs were distinguished that can be used as diagnostics as well as prognostic markers for breast cancer.

Absolute lymphocyte count decreases with disease progression and is a potential prognostic marker for metastatic breast cancer.

Peripheral blood parameters such as the neutrophil-to-lymphocyte ratio (NLR) are prognostic markers for breast cancer patients. For instance, patients with a high NLR have a poor prognosis. Meanwhile, high absolute lymphocyte count (ALC) is reportedly a predictive factor for some chemotherapies. However, the underlying mechanisms behind how these markers relate to patient outcomes and how these markers change during the clinical course of patients with metastatic breast cancer (MBC) remains unknown. We retrospectively investigated 156 patients who were treated for MBC and eventually transitioned to best supportive care (BSC) at our hospital between January 2017 and December 2021. Changes in peripheral blood parameters during MBC treatments and their association with patient outcomes were examined. From the time of MBC diagnosis (baseline) through to the transition to BSC, ALC became significantly lower, while the NLR and platelet-to-lymphocyte ratio (PLR) became significantly higher (p < 0.001 for all). This association was independent of hormone receptor status. Cox proportional hazard modeling found patients with hormone receptor-negative and a lower baseline ALC had a significantly shorter overall survival (p = 0.030 and p = 0.019, respectively). We observed that peripheral blood markers gradually changed with MBC disease progression. Our data suggest that baseline ALC may be a potential prognostic marker after recurrence.

Role of mitochondrial translation in remodeling of energy metabolism in ER/PR(+) breast cancer.

Remodeling of mitochondrial energy metabolism is essential for the survival of tumor cells in limited nutrient availability and hypoxic conditions. Defects in oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis also cause a switch in energy metabolism from oxidative to aerobic glycolysis contributing to the tumor heterogeneity in cancer. Specifically, the aberrant expressions of mitochondrial translation components such as ribosomal proteins (MRPs) and translation factors have been increasingly associated with many different cancers including breast cancer. The mitochondrial translation is responsible for the synthesis 13 of mitochondrial-encoded OXPHOS subunits of complexes. In this study, we investigated the contribution of mitochondrial translation in the remodeling of oxidative energy metabolism through altered expression of OXPHOS subunits in 26 ER/PR(+) breast tumors. We observed a significant correlation between the changes in the expression of mitochondrial translation-related proteins and OXPHOS subunits in the majority of the ER/PR(+) breast tumors and breast cancer cell lines. The reduced expression of OXPHOS and mitochondrial translation components also correlated well with the changes in epithelial-mesenchymal transition (EMT) markers, E-cadherin (CHD1), and vimentin (VIM) in the ER/PR(+) tumor biopsies. Data mining analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) breast cancer proteome further supported the correlation between the reduced OXPHOS subunit expression and increased EMT and metastatic marker expression in the majority of the ER/PR(+) tumors. Therefore, understanding the role of MRPs in the remodeling of energy metabolism will be essential in the characterization of heterogeneity at the molecular level and serve as diagnostic and prognostic markers in breast cancer.

Knockdown of CKAP2 Inhibits Proliferation, Migration, and Aggregate Formation in Aggressive Breast Cancer.

Simple SummaryCancer is a complex disease where cells grow and divide in an uncontrolled manner. It is well established that its development and progression involve major alterations in the activity of mitotic regulators. In order to improve our understanding of the contribution of cell-cycle progression defects to the development of disease, the aim of this study is to identify genes relevant to the proper progression of mitosis that are deregulated in breast cancer. Our findings identified CKAP2 as an important mitotic regulator in BC tumors. Moreover, in vitro experiments showed that gene silencing of CKAP2 blocked cell growth, cell migration, and formation of cell aggregates. These results demonstrated the important role of CKAP2 in breast cancer tumor formation.Loss of mitotic regulation is commonly observed in cancer and is a major cause of whole-chromosome aneuploidy. The identification of genes that play a role in the proper progression of mitosis can help us to understand the development and evolution of this disease. Here, we generated a list of proteins implicated in mitosis that we used to probe a patient-derived breast cancer (BC) continuum gene-expression dataset generated by our group by human transcriptome analysis of breast lesions of varying aggressiveness (from normal to invasive). We identified cytoskeleton-associated protein 2 (CKAP2) as an important mitotic regulator in invasive BC. The results showed that CKAP2 is overexpressed in invasive BC tumors when compared with normal tissues, and highly expressed in all BC subtypes. Higher expression of CKAP2 is also related to a worse prognosis in overall survival and relapse-free survival in estrogen receptor (ER)-positive and human epidermal growth factor receptor type 2 (HER2)-negative BC patients. Knockdown of CKAP2 in SKBR3 cells impaired cell proliferation and cell migration and reduced aggregate formation in a 3D culture. Our results show the important role of CKAP2 in BC tumorigenesis, and its potential utility as a prognostic marker in BC.

CCDC69 is a prognostic marker of breast cancer and correlates with tumor immune cell infiltration.

PurposeBreast cancer (BC) is the most common malignancy and the leading cause of cancer-related death among women worldwide. Early detection, treatment, and metastasis monitoring are very important for the prognosis of BC patients. Therefore, effective biomarkers need to be explored to help monitor the prognosis of BC patients and guide treatment decisions.MethodsIn this study, the relationship between CCDC69 expression levels and tumor clinical characteristics were analyzed using RNA-seq information in BC samples from the TCGA database. Kaplan-Meier survival analysis was performed to analyze the prognostic value of CCDC69 in BC patients. Besides, gene enrichment analysis in BC samples was used to confirm the main function of CCDC69 in BC. The correlation between the expression of CCDC69 and the number of tumor-infiltrating lymphocytes was confirmed by interaction analysis of TIMER and GEPIA.ResultsThe results showed that CCDC69 expression was significantly lower in cancer samples than in normal tissues, and was significantly lower in highly invasive BC than in carcinoma in situ. Meanwhile, low levels of CCDC69 were associated with a further poor prognosis. CDCC69 expression was positively correlated with the amount of different tumor-infiltrating lymphocytes. Mechanically, it could be presumed that the low expression of CCDC69 in BC might be caused by hypermethylation of the promoter region.ConclusionsSummarily, CDCC69 could be used as a potential biomarker to predict the prognosis of BC and the sensitivity to immunotherapy such as PD-1/PD-L1 checkpoint inhibitors.

Identification of UCP1 and UCP2 as Potential Prognostic Markers in Breast Cancer: A Study Based on Immunohistochemical Analysis and Bioinformatics.

Background: Uncoupling protein 1 (UCP1) and UCP2 are associated with tumor metabolism and immunity. However, the prognostic value and molecular mechanisms underlying their action in breast cancer (BC) remain unclear. Materials and methods: In TCGA-BRCA cohort, we investigated the expression characteristics of UCP mRNAs, analyzed their prognostic value by Kaplan-Meier survival analysis, their potential molecular functions by gene set enrichment analysis, and their relationship with immune infiltrating cell types using TIMER and CIBERSORT, along with the assessment of their association with mutational profiles. Kaplan-Meier survival analysis was performed for UCPs in our cohort and their association with BC thermogenesis was assessed by thermal tomography. Results: High expression of UCP1 and UCP2 were positive prognostic markers for BC. UCP1 was associated with the impaired glucose metabolism, while UCP2 with enhanced anti-tumor immunity. High expressions of UCP1 and UCP2 were associated with CDH1 mutations. High UCP1 expression was associated with a high rate of thermogenesis in BC. Conclusions: These results implied a key role of UCP1 and UCP2 in prognosis, metabolism, and immune infiltration in BC. Further investigation of the relevant molecular mechanisms may provide new strategies for BC treatment.

Correlation of 18-fluorodeoxyglucose uptake values on PET-CT scan with histological prognostic markers in breast cancer.

Positron emission tomography-computed tomography (PET-CT) scan utilizes 18-fluorodeoxyglucose (18-FDG), based on the principle of higher glycolytic activity and reduced glucose-6-phosphatase levels in cancer cells. This imaging modality is usually advised in the metastatic evaluation of stage III breast cancer patients. The correlation of maximum standard uptake values of primary lesion with different pathological and molecular markers has not been studied extensively. Retrospective analysis of the data was performed from our prospectively maintained breast cancer database. All the patients who had undergone 18-FDG PET-CT scan at initial evaluation for staging between June 2017 and April 2020 were included in the study. One-way ANOVA test or Student's t-test as appropriate was performed to assess the difference of means in maximum standard uptake values (SUVmax) of the primary lesion and axillary nodes with clinical stage, histological grade, molecular subtype. Bonferroni post hoc test was also applied. Out of 388 patients in the breast cancer database, 45 patients met inclusion criteria. There was a significant correlation of molecular subtype (p=0.029) with SUVmax of the primary lesion. Higher primary SUVmax was associated with higher T stage (p=0.01) and higher histological grade (p=0.06). In each molecular subtype, there was an increase in mean SUVmax of the primary lesion with increasing histological grade and vice versa. SUVmax of the primary lesion in breast cancer patients reflects tumor biology. Higher SUVmax can predict patients with triple-negative breast cancers and higher grades in primary tumors. However, further large-scale validatory studies are essential.

Dissecting the Roles of PDCD4 in Breast Cancer.

The human programmed cell death 4 (PDCD4) gene was mapped at chromosome 10q24 and encodes the PDCD4 protein comprised of 469 amino acids. PDCD4 inhibits protein translation PDCD4 inhibits protein translation to suppress tumor progression, and its expression is frequently decreased in breast cancer. PDCD4 blocks translation initiation complex by binding eIF4A via MA-3 domains or by directly binding 5’ mRNA internal ribosome entry sites with an RNA binding domain to suppress breast cancer progression and proliferation. Numerous regulators and biological processes including non-coding RNAs, proteasomes, estrogen, natural compounds and inflammation control PDCD4 expression in breast cancer. Loss of PDCD4 expression is also responsible for drug resistance in breast cancer. HER2 activation downregulates PDCD4 expression by activating MAPK, AKT, and miR-21 in aromatase inhibitor-resistant breast cancer cells. Moreover, modulating the microRNA/PDCD4 axis maybe an effective strategy for overcoming chemoresistance in breast cancer. Down-regulation of PDCD4 is significantly associated with short overall survival of patients, which suggests that PDCD4 may be an independent prognostic marker for breast cancer.

Integrated analysis of pivotal biomarker of LSM1, immune cell infiltration and therapeutic drugs in breast cancer.

The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Here, the expression of LSM1 mRNA in breast cancer was estimated using The Cancer Genome Atlas (TCGA), Oncomine, TIMER and bc‐GenExMiner databases. We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in breast cancer (BRCA) patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease‐free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer.

Integrated analysis of pivotal biomarker, immune cell infiltration, and therapeutic drugs for LSM1-mutated in breast cancer.

e13011 Background: The discovery of early diagnosis and prognostic markers for breast cancer can significantly improve survival and reduce mortality. LSM1 is known to be involved in the general process of mRNA degradation in complexes containing LSm subunits, but the molecular and biological functions in breast cancer remain unclear. Methods: In the present study, we investigated the expression profiles, prognostic roles, and genetic alterations of LSM1 in patients with breast cancer through several public databases, containing Oncomine and Gene Expression Profiling Interactive Analysis, Human Protein Atlas, Kaplan–Meier plotter and cBioPortal. Then, we constructed the protein-protein interaction networks of LSM1 proteins and their interactors by using the String database and Cytoscape software. In addition, we performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichmente. Finally, we explored the mechanisms underlying LSM1 involvement in BRCA by using gene set enrichment analysis. Results: We found that functional LSM1 inactivation caused by mutations and profound deletions predicted poor prognosis in BRCA patients. LSM1 was highly expressed in both BRCA tissues and cells compared to normal breast tissues/cells. High LSM1 expression is associated with poorer overall survival and disease-free survival. The association between LSM1 and immune infiltration of breast cancer was assessed by TIMER and CIBERSORT algorithms. LSM1 showed a strong correlation with various immune marker sets. Most importantly, pharmacogenetic analysis of BRCA cell lines revealed that LSM1 inactivation was associated with increased sensitivity to refametinib, and trametinib. However, both drugs could mimic the effects of LSM1 inhibition and their drug sensitivity was associated with MEK molecules. Therefore, we investigated the clinical application of LSM1 to provide a basis for sensitive diagnosis, prognosis and targeted treatment of breast cancer. Conclusions: In brief, our finding may contribute to increasing currently limited prognostic biomarkers and treatment options for breast cancer.