Breast Cancer Tumor Tissues Research Articles

Effect of caspase-1 (CASP1) combined with multimodal ultrasound features on the prognosis of breast cancer patients.

Breast cancer (BRCA) is the malignant tumor with the highest incidence rate among women in the world, and its mortality rate ranks second. The purpose of our study is to explore the correlation between caspase-1 (CASP1) and the prognosis of BRCA patients and the potential mechanism of action, and to analyze the clinical value of CASP1 combined with multimodal ultrasound features in early screening and prognosis of BRCA. We analyzed The Cancer Genome Atlas (TCGA) database to confirm that CASP1 was expressed in BRCA patients and determine whether its expression was correlated with patient prognosis. The relationship between CASP1 expression and survival was measured by the clinicopathological parameters. Multivariate analysis was performed using Cox regression, and a nomogram was developed using these results for quality assurance purposes. The correlations between CASP1 and immune cells were investigated using the Tumor Immune Estimation Resource (TIMER) and TCGA databases. Next, we performed gene set enrichment analysis (GSEA) to determine the potential mechanism of action. Finally, to analyze the effect of CASP1 combined with multimodal ultrasonography characteristics on the prognosis of BRCA patients was studied by analyzing the clinical data of patients. CASP1 expression was lower in BRCA tumor tissues than in the surrounding tissues. Patients with high CASP1 expression had better overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) than those with low CASP1 expression. GSEA suggested that CASP1 may affect the cell cycle, immune environment, inflammation, apoptosis, the HIPPOMERLIN pathway, Natural killer (NK) cell regulation of cytotoxicity, p53 expression, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, the mitogen-activated protein kinase (MAPK) pathway, extracellular matrix, etc., thereby influencing the biological events in BRCA. Among conventional ultrasound features and contrast-enhanced ultrasound (CEUS) features, mass margin status and blood flow grade were associated with the expression of CASP1. Meanwhile, patients with poor ultrasound features tended to have low CASP1 expression. CASP1 may be a novel predictive marker for BRCA patients. CASP1 combined with multimodal ultrasound features has good clinical value in the early screening and prognostic prediction of BRCA.

The relationship between tissue differentiation-inducing non-protein coding RNA expression and tumor size in patients with breast cancer.

Cancer is one of the leading causes of human death worldwide. One of the most common types of malignancy among women is breast cancer, which is the third most common cancer in the world after lung and stomach cancer. This study aimed to evaluate the expression level of Tissue Differentiation-Inducing Non-Protein Coding RNA (TINCR) in adjacent tumor and non-tumor tissues of 60 women with invasive ductal breast cancer. The relationship between TINCR expression and the clinical characteristics of patients has also been studied. For this purpose, total RNA was isolated from breast cancer patients' adjacent tumor and non-tumor tissue. RT Prime Script reagent was then used to convert total RNA to cDNA. The qRT-PCR quantified the TINCR expression level and analyzed the results by paired t-test. In addition, ROC curve analysis was used to evaluate the biomarker power of TINCR in breast cancer tumor tissues. According to the results, a decrease in the level of TINCR was obtained in the tumor tissue of breast cancer patients compared to the adjacent non-tumor tissue (P<0.001). TINCR expression was negatively correlated with tumor size and lymph node metastasis in breast cancer tumor tissue. In general, the decrease in the expression level of TINCR in the tumor tissue of breast cancer patients shows that its expression level can differentiate the adjacent tumor and non-tumor tissue from each other. In addition, TINCR has a lower expression level in breast cancer patients with large tumors, lymph node metastasis, and luminal subgroups A and B.

In Silico and Experimental Outcomes of the Expression of miR508-5p and miR-635 in Tumor Tissues of Patients with Breast Cancer

Background: Breast cancer (BC) is a malignant tumor that occurs in the epithelial tissue of the breast gland and has become the most common malignancy in women. Various studies have reported the effect of epigenetic changes, including DNA methylation and microRNAs, on breast carcinogenesis. microRNAs play an important role in the post-transcriptional regulation of genes and are important regulators of oncogenic pathways. Studying microRNAs in BC facilitates the development of targeted therapies and early detection of this cancer. Objectives: This study aimed to evaluate the expression level of miR-508-5p and miR-635 in BC tumor tissues compared to healthy marginal tissues. Methods: In silico analysis confirmed microarray datasets (GSE40525, GSE44124 and GSE45666) downloaded from the GEO database. The analysis was defined using the Affy packages in R software to screen remarkably dysregulated miRNAs attended by utilized to predict the potential biological processes and molecular pathways of miR-508-5p and miR-635. Experimental statistical significance of differences in miRNA relative expression results was analyzed by pair-wise fixed reallocation randomization test as a statistical model included in the REST (relative expression software tool). Results: GEO microarray data set, similar to qPCR results, showed that miR-508-5p was downregulated in the sample group by a mean factor of 0.327 (S.E.M range is 0.031-2.000). Moreover, miR-635 was upregulated in the sample group by a mean factor of 2.361 (S.E.M range is 0.250-16.000). Conclusion: miR-508-5p was downregulated, while miR-635 was upregulated in BC tissues. They may be proposed as diagnostic and therapeutic biomarkers for patients with BC.

Novel Method to Obtain Contact Angles of Tumor Biopsies.

Characterizing the strength of a solid-liquid interface can be done by depositing a single drop of liquid on a planar solid surface and measuring the angle of the formed semicircle, called the contact angle. The contact angle of pure water is indicative of a surface's hydrophobicity and is a useful metric in biomedical applications such as tissue scaffolding and drug/tissue interactions. However, the roughness and inhomogeneity of most biological surfaces make obtaining accurate contact angles of such materials challenging. Here, we developed an instrument and methodology to obtain contact angles of tissue sections. Breast cancer tumor and nearby healthy tissue sections were used as the model biological surface. The custom instrument was built on existing equipment by improving drop dispensing accuracy in the nanoliter range, an XYZ stage, additional side view cameras, and microscope-based sample visualization. The method takes into account the inherent surface inhomogeneity and topology of tissue and the required method of illumination for contact angle acquisition. As such, the system uses an inverted microscope with a high sensitivity camera, an XYZ stage for accurate droplet placement on tissue, and multiple cameras to obtain contact angles around the entire perimeter of the drop. We tested the system with breast cancer biopsies and adjacent normal tissue from 75 patients and report here a trend of tumor exhibiting higher water contact angles, and thus higher hydrophobicity, compared to their respective normal adjacent tissue. The system described here can be used to characterize any type of biological tissue, which can be sectioned, with any liquid including water or solutions with dissolved or suspended therapeutic molecules and particles.

High electrochemical active Au-NP/2D zinc-metal organic frameworks heterostructure-based ECL sensor for the miRNA-522 detection in triple negative breast cancer

In this work, a novel electrochemiluminescence (ECL) sensor has been developed to detect the miRNA-522 in the tumor tissues of triple-negative breast cancer (TNBC) patients. Au NPs/Zn MOF heterostructure was obtained by in situ growth and used as novel luminescence probe. Firstly, zinc-metal organic framework nanosheets (Zn MOF NSs) were synthesized with Zn2+ as the central metal ion and 2-aminoterephthalic acid (NH2-BDC) as the ligand. 2D MOF nanosheets with ultra-thin layered structure and relatively large specific surface areas can enhance the catalytic activity in the ECL generation. Furthermore, the electron transfer capacity and the electrochemical active surface area of MOF were greatly improved by the growth of Au NPs. Therefore, Au NPs/Zn MOF heterostructure showed the significant electrochemical activity in the sensing process. In addition, the magnetic Fe3O4@SiO2@Au microspheres were used as capture units in the magnetic separation step. The magnetic spheres with hairpin aptamer H1 can capture target gene. Then the captured miRNA-522 triggered the target catalyzed hairpin assembly (CHA) sensing process and linked Au NPs/Zn MOF heterostructure. The concentration of miRNA-522 can be quantified by the ECL signal enhancement of the Au NPs/Zn MOF heterostructure. Due to the high catalytic activity of Au NPs/Zn MOF heterostructure and their unique structural and electrochemical properties, the prepared ECL sensor achieved high-sensitive detection of miRNA-522 in the range of 1 fM to 0.1 nM with the detection limit of 0.3 fM. This strategy can provide a potential alternative for miRNA detection in medical research and clinical diagnosis of triple negative breast cancer.

Circ_ATAD3B inhibits cell proliferation of breast cancer via mediating the miR-570-3p/MX2 axis

It has been discovered that some circular RNAs can serve as excellent therapeutic targets for breast cancer (BC). However, the biological role that circ ATAD3B plays in BC is not yet completely understood. As a result, the purpose of this work was to evaluate the function of circ_ATAD3B in the development of BC. Three different GEO datasets were used to compile the expression profiles of circRNAs related to BC (GSE101124, GSE165884, and GSE182471). CCK-8 and the production of clones, in addition to RT-PCR and western blot assays, were utilized in this study to evaluate the regulation of these three biological molecules in the process of BC carcinogenesis.circ_ATAD3B was the only potential BC-related circRNA that was significantly reduced in BC tumor tissues, and it functioned as a miR-570-3p sponge to suppress cell survival and proliferation, as stated by the aforementioned two algorithms. The expression of MX2 was boosted when circ_ATAD3B was used to sponge miR-570-3p. The inhibitory effect that circ_ATAD3B has on the malignant phenotype of BC cells was overcome by the expression of miR-570-3p through up-regulation and MX2 through down-regulation. The tumor suppressor circ_ATAD3B prevents cancer progression by regulating the miR-570-3p/MX2 pathway. Circ_ATAD3B may be a candidate for targeted therapy of breast cancer.

Identification of a novel glycolysis-related prognosis risk signature in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive cluster of breast cancer characterized by significant molecular heterogeneity. Glycolysis is a metabolic pathway that is significantly associated with cancer progression, metastasis, recurrence and chemoresistance. However, the potential roles of glycolysis-related genes in TNBC remain unclear. In the present study, we identified 108 glycolysis-related differentially expressed genes (DEGs) between breast cancer (BRCA) tumor tissues and normal tissues, and we divided patients into two different clusters with significantly distinct molecular characteristics, clinicopathological features, prognosis, immune cell infiltration and mutation burden. We then constructed a 10-gene signature that classified all TNBCs into low- and high-risk groups. The high-risk group had significantly lower survival than the low-risk group, which implied that the risk score was an independent prognostic indicator for TNBC patients. Consequently, we constructed and validated a prognostic nomogram, which accurately predicted individual overall survival (OS) of TNBC. Moreover, the risk score predicted the drug sensitivity of chemotherapeutic agents and immunotherapy for TNBC patients. The present comprehensive analysis of glycolysis-related DEGs in TNBC provides new methods for prognosis prediction and more effective treatment strategies.

Abstract 308: Low molecular weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer

Abstract Background: Low molecular weight cyclin E (LMW-E) are oncogenic forms of cyclin E that are post translationally generated from the full-length cyclin E1 (FL-cycE). LMW-E is detected in breast cancer cells and tumor tissues, but not in normal mammary epithelial cells or adjacent normal tissues. Unlike FL-cycE, LMW-E drives mammary epithelial cell transformation in human cells and spontaneous mammary tumor formation in transgenic mouse models, but the oncogenic mechanisms of LMW-E and its unique function(s) independent of FL-cycE are not fully understood. It is currently assumed that LMW-E drives the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Biochemical features such as longer protein half-life, higher affinity to its kinase partner CDK2, and resistance to endogenous CDK inhibitors such as p21 and p27 all promote the tumorigenic ability of LMW-E. Clinical studies in breast cancer reveal that overexpression of LMW-E predicts recurrence and poor survival in breast cancer patients independent of molecular subtype, Ki67 status, nodal status, or tumor grade, suggesting LMW-E may drive breast cancer development independent of its role in cell proliferation. In the current study, we tested the hypothesis that LMW-E promotes genomic instability by deregulating DNA replication and damage repair. Results: We generated immortalized pre-cancerous human mammary epithelial cells (hMECs) to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background. We found that FL-cycE overexpression led to DNA replication stress and DNA damage accumulation, resulting in reduced cell viability. LMW-E overexpression, on the other hand, promoted cell survival under replication stress, resulting in persistent genomic instability. RNA-sequencing results showed LMW-E but not FL-cycE overexpression enhanced DNA replication and damage repair pathways. Molecularly, LMW-E interacted with and facilitated pre-replication complex assembly. LMW-E also mediated DNA repair by upregulating RAD51 and C17orf53, showing a dominant repairing effect over DNA damage induced by FL-cycE. Moreover, targeting the replication stress response pathway ATR-CHK1-RAD51 with small molecule inhibitors significantly decreased viability of LMW-E overexpressing hMECs and breast cancer cells. Lastly, we showed that positive LMW-E status was associated with genomic instability in tumors from a cohort of 725 patients diagnosed with early-stage breast cancer, further supporting our hypothesis that LMW-E promotes genomic instability to fuel breast cancer development. Conclusions: Collectively, our findings delineated a novel role for LMW-E in breast tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E overexpressing breast cancers. Citation Format: Mi Li, Spiridon Tsavachidis, Fuchenchu Wang, Tuyen Bui, Tuyen D. Nguyen, Linjie Luo, Asha S. Multani, Melissa L. Bondy, Kelly K. Hunt, Khandan Keyomarsi. Low molecular weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 308.

Abstract P2-03-04: Long-Term Benefit from Adjuvant Tamoxifen in Luminal A and Luminal B Breast Cancer Patients

Abstract Background: The risk for patients with estrogen receptor (ER)-positive breast cancer remains stable decades after primary diagnosis, with a large proportion of distant metastatic events occurring late. Thus, long-term follow-up studies are essential to understand true treatment benefit. Tamoxifen (TAM) therapy is a fundamental endocrine treatment for ER-positive breast cancer. We have previously shown a long-term tamoxifen therapy benefit for patients with less aggressive tumor characteristics in ER-positive/HER2-negative patients. However, ER-positive breast cancer is highly heterogenous and can be separated into different molecular subpopulations that behave differently during extended follow-up. The long-term tamoxifen benefit by molecular subtype is largely unexplored. We therefore aimed to investigate the long-term benefit from tamoxifen by clinically used tumor characteristics in Luminal A vs Luminal B patients in the Stockholm tamoxifen (STO)-trials with complete 20-years follow-up. Methods: Secondary analysis of ER-positive/HER2-negative patients with Luminal A or B molecular subtype (n=952) from the STO-trials (1976-1997) randomized to TAM (40 mg) vs no endocrine therapy (control). Gene expression data was generated using custom designed Agilent arrays from FFPE breast cancer tumor tissue and was used to define PAM50 molecular subtypes. The clinically used markers were reannotated in 2014 and 2020. Complete 20-year follow-up was obtained from Swedish high-qualitative registries. The long-term distant recurrence-free interval (DRFI) was assessed by Kaplan-Meier, multivariable Cox proportional hazard regression and time-varying analysis, using flexible parametric modelling. Results: Multivariable analysis showed significantly improved long-term DRFI from TAM vs control for both Luminal A (HR=0.59; 95% CI, 0.44-0.81) and Luminal B (HR=0.67; 95% CI, 0.46-0.99) patients. Time-varying analysis showed that patients with Luminal A subtype significantly benefitted from TAM for 15 years (HR=0.60, 95% CI, 0.39-0.94 at year 15), whereas patients with Luminal B subtype had a significant TAM benefit for 5 years (HR=0.64, 95% CI, 0.42-0.98 at year 5), see Table. Furthermore, a significant long-term TAM benefit for patients with large tumor size (pT&amp;gt;20mm: HR=0.46; 95% CI, 0.25-0.84), tumor grade 1-2 (HR=0.55; 95% CI, 0.40-0.77), lymph node-negative (HR=0.51, 95% CI, 0.34-0.78), PR-positive (HR=0.57, 95% CI, 0.40-0.81) and Ki-67-low tumors (HR=0.55, 95% CI, 0.39-0.77) was seen for Luminal A patients. In Luminal B patients, significantly improved long-term DRFI from TAM vs control was seen for small tumor size (pT≤20mm: HR=0.44; 95% CI, 0.24-0.80), tumor grade 1-2 (HR=0.51; 95% CI, 0.29-0.90), lymph node-negative (HR=0.40, 95% CI, 0.19-0.83), PR-positive (HR=0.59, 95% CI, 0.38-0.93) and Ki-67-low tumors (HR=0.45, 95% CI, 0.25-0.84). Conclusions: This study suggests a 15 years tamoxifen benefit for patients with Luminal A subtype tumors, whereas the benefit for patients with Luminal B tumors is up to five years after diagnosis. Furthermore, our study suggests a long-term tamoxifen benefit for patients with less aggressive tumor characteristics regardless of tumor subtype, except for tumor size in Luminal A patients. ER-positive breast cancer is a heterogeneous disease and long-term follow-up studies in molecular subtypes are essential to understand differences in treatment benefit. Table. Time-varying analysis of long-term tamoxifen therapy benefit by PAM50 molecular subtype. Time-varying analysis of distant recurrence-free interval (DRFI) to assess how tamoxifen benefit varied over the 20 year of follow-up using flexible parametric survival modelling. Patients included in analyses with no missing values. Estimated hazard ratios (HR) at year 5, 10, 15 and 20 for patients with Luminal A or Luminal B molecular subtype tumors randomized to tamoxifen therapy, as compared with patients randomized to no endocrine therapy (control). Adjusted for age, period of primary breast cancer diagnosis, tumor size, tumor grade, lymph node status, PR status, Ki-67 status, chemotherapy, radiotherapy, type of surgery, and menopausal status. *indicates significant findings P&amp;lt;0.05 Citation Format: Huma Dar, Annelie Johansson, Anna Nordenskjöld, Gizeh Perez-Tenorio, Christina Yau, Christopher C. Benz, Laura J. Esserman, Bo Nordenskjöld, Olle Stål, Tommy Fornander, Linda S. Lindström. Long-Term Benefit from Adjuvant Tamoxifen in Luminal A and Luminal B Breast Cancer Patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-03-04.

Predictive significance of HIF-1α, Snail, and PD-L1 expression in breast cancer.

Currently, the prediction of breast cancer (BC) effectiveness to drug treatment is based on determining the expression level of steroid hormone receptors and human epidermal growth factor receptor type 2 (HER2). However, significant differences in individual response to drug treatment require the search for new predictive markers. Here, by comprehensively examining HIF-1α, Snail, and PD-L1 expression in BC tumor tissue, we demonstrate that high levels of these markers correlate with unfavorable factors of BC prognosis: the presence of regional and distant metastases and lymphovascular and perineural invasion. Analyzing the predictive significance of markers, we show that the most significant predictors of chemoresistant HER2-negative BC are a high PD-L1 level and a low Snail level, while in HER2-positive BC, only a high PD-L1 level is an independent predictor of chemoresistant BC. Our results suggest that using immune checkpoint inhibitors in these groups of patients may improve drug therapy effectiveness.

Downregulation of MICA/B tumor surface expressions and augmented soluble MICA serum levels correlate with disease stage in breast cancer.

In this study, the profiling of the expression of major histocompatibility complex (MHC) class I-related chain A and B (MICA/B) in human breast cancer tumor tissue, saliva, and urine samples of breast cancer patients and control is carried out. MICA/B is ligand of NKG2D receptor expressed on malignant cells. The release of MICA/B from tumor tissue comprises an immune escape mechanism that impairs antitumor immunity. Based on this literature we explored the potential of soluble MICA (sMICA) as a marker in breast cancer (BC). The expression was profiled by using immunohistochemistry (MICA/B), western blot (MICA/B) and ELISA (MICA). The optical density of western blot of MICA/B in different stages of BC illustrated significant difference as per one way analysis of variance and significant difference with stage III and IV by Dunnett's multiple comparisons test respectively. Analysis of sMICA in serum, saliva and urine of BC patients revealed significantly higher levels (median 41.0 ± 4.1 pg/ml in pre-treatment sera, 181.9 ± 1.6 pg/ml in saliva and 90.7 ± 1.7 pg/ml in urine) than in control (median <1.2 pg/ml). The elevated levels of sMICA were related to the cancer stage. The elevated levels of sMICA were observed in patients with well differentiated cancer while the poor expression of sMICA was observed in patients with poorly differentiated tumors. Tumor immunity is impaired by the release of MICA in the biofluids and may be useful for detection and diagnosis of the stage of BC.

Association between KRAS gene polymorphisms and genetic susceptibility to breast cancer in a Chinese population.

The KRAS gene has a pathophysiological role in the development of many cancers. This study aims to investigate the relationship between KRAS polymorphisms and genetic susceptibility to breast cancer. The rs712, rs12587 and rs9266 gene loci in the KRAS gene of 421 subjects (141 breast cancer patients, 141 benign breast tumours and 139 healthy controls) were analysed by the polymerase chain reaction and SNaPshot sequencing. Transcriptomic information on KRAS and corresponding clinical information was downloaded from the TCGA and GTEx databases. Differences in KRAS expression between breast cancer tissues and control tissues were analysed. We found no significant association between KRAS rs712 and rs12587 locus gene polymorphisms and an increased risk of developing benign breast tumours and breast cancer (p > 0.05). The KRAS rs9266 locus mutation heterozygous model CT and dominant model CT + TT were significantly associated with an increased risk of breast cancer (both p < 0.05). In addition, the TAT haplotype was expressed at an increased frequency, and the GAC haplotype was expressed at a reduced frequency in breast cancer compared with controls (both p < 0.05). We found that KRAS was over expressed in breast cancer tumour tissues compared with the control tissues (p < 0.0001). The KRAS rs9266 gene polymorphism and the TAT haplotype may be associated with an increased risk of breast cancer in Chinese women. The GAC haplotype may be a protective factor against breast cancer.

DNMT3B and TET1 mediated DNA methylation of LATS1 regulates BC progression via hippo signaling pathway.

Large tumor suppressor gene 1 (LATS1) is one of the key proteins in the Hippo signaling pathway, which plays a role in inhibiting tumor progression, but its anti-tumor role in tumors is inhibited. Nevertheless, the specific molecular mechanism of its role in breast cancer (BC) are still unclear. The expression of LATS1 in BC was detected by RT-qCR and WB. The biological effect of LATS1 on BC was verified in vitro and in vivo. DNA methylation sequencing and MSP were used to detect the effect of DNMT3B and TET1 on LATS1 methylation. Analysis of the effect of DNMT3B and TET1 on the biological behavior of BC cells via LATS1 by cell function experiment. Results indicated that the expression of LATS1 is lower in BC tumor tissues and BC cell lines. low LATS1 expression BC patients have a shorter overall survival. Increasing LATS1 expression can inhibit the proliferation, migration and invasion of BC. LATS1 found to have high DNA methylation changes in the promoter region. Moreover, DNMT3B was increased in BC tissues, and DNA demethylase TET1 was decreased in BC tissues. Furthermore, DNMT3B and TET1 regulate the methylation of LATS1, and methylation of LATS1 inactivates Hippo signaling pathway. Our results indicate that the methylation of LATS1 is regulated by DNMT3B and TET1 and regulates its protein expression and the function of Hippo signaling pathway.

The controllable assembly of Cu nanocluster-based aggregation induced ECL strategy for miRNA detection

Copper nanoclusters (Cu NCs) were a new class of non-toxic and economical nanoprobe. However, the low luminescence performance and instability of Cu NCs limited the actual application. Herein, this work developed the novel controllable assembly of Cu NCs aggregation as the electrochemiluminescence (ECL) emitter. Firstly, the hydrophilic Cu NCs was located into the micelles in the reverse microemulsion system. Due to the uniform size of micelles, the number of Cu NCs in each micelle can be controlled exactly. Cerium ions were added to induce Cu NCs to accumulate in micelles. The strong aggregation induced ECL (AIECL) signal can be observed in the controllable assembly of Cu NCs aggregation. The nano-sized Cu NCs assembly not only possessed more strong luminescence and better stability than original Cu NCs, but also kept the good dispersibility over the aggregated bulk. Furthermore, SnS2 nanosheets increased the specific surface area of the electrode and the number of reactive sites, which further modulated electron transfer to amplify the ECL signal. The ECL sensing system was used to detect miRNA-455–3p in the triple-negative breast cancer tumor tissues. The work provided the new pathway to prepare Cu NCs assembly and expanded AIECL-based sensing application.

TRIM35 ubiquitination regulates the expression of PKM2 tetramer and dimer and affects the malignant behaviour of breast cancer by regulating the Warburg effect.

Breast cancer has become the leading cause of death in females. After comprehensive treatment, the lives of patients are still threatened by tumor metastasis and recurrence. Therefore, there is an urgent requirement to find an effective treatment target for breast cancer. Tripartite motif-containing 35 (TRIM35) is a ubiquitin ligase that has an important role in the recurrence and metastasis of malignant tumors. However, the role of TRIM35 in breast cancer has thus far remained elusive. The expression of TRIM35 was examined in a bioinformatics database and the effects of TRIM35 on the malignant biological behavior of breast cancer were analyzed by Cell Counting Kit-8, cell migration and invasion assays, flow cytometry and nude mouse xenograft experiments. It was determined that TRIM35 was downregulated in breast cancer tumor tissues and cell lines. Patients with low TRIM35 expression had shorter overall survival. Functional assays revealed that overexpression of TRIM35 inhibited the proliferation, migration and invasion, and promoted apoptosis of breast cancer cells. Furthermore, overexpression of TRIM35 was able to inhibit the Warburg effect in breast cancer cells. Mechanistic analyses indicated that TRIM35 regulates the transition of tetramers and dimers of pyruvate kinase M2 (PKM2) through ubiquitination and thereby affects the Warburg effect. In conclusion, the present results indicated that TRIM35 regulates the tetramer and dimer transition of PKM2 through ubiquitination and affects the malignant biological behavior of breast cancer by modulating the Warburg effect.

Growth-promoting function of the cGAS-STING pathway in triple-negative breast cancer cells.

The cGAS-STING axis is one of the key mechanisms guarding cells from pathogen invasion in the cytoplasmic compartment. Sensing of foreign DNA in the cytosol by the cGAS-STING axis triggers a stress cascade, culminating at stimulation of the protein kinase TBK1 and subsequently activation of inflammatory response. In cancer cells, aberrant metabolism of the genomic DNA induced by the hostile milieu of tumor microenvironment or stresses brought about by cancer therapeutics are the major causes of the presence of nuclear DNA in the cytosol, which subsequently triggers a stress response. However, how the advanced tumors perceive and tolerate the potentially detrimental effects of cytosolic DNA remains unclear. Here we show that growth limitation by serum starvation activated the cGAS-STING pathway in breast cancer cells, and inhibition of cGAS-STING resulted in cell death through an autophagy-dependent mechanism. These results suggest that, instead of being subject to growth inhibition, tumors exploit the cGAS-STING axis and turn it to a survival advantage in the stressful microenvironment, providing a new therapeutic opportunity against advanced cancer. Concomitant inhibition of the cGAS-STING axis and growth factor signaling mediated by the epidermal growth factor receptor (EGFR) synergistically suppressed the development of tumor organoids derived from primary tumor tissues of triple-negative breast cancer (TNBC). The current study unveils an unexpected function of the cGAS-STING axis in promoting cancer cell survival and the potential of developing the stress-responding pathway as a therapeutic target, meanwhile highlights the substantial concerns of enhancing the pathway’s activity as a means of anti-cancer treatment.

Confined Gold Single Atoms-MXene Heterostructure-Based Electrochemiluminescence Functional Material and Its Sensing Application.

Herein, based on electronic metal-support interaction (EMSI), a gold single atom confined MXene (AuSA/MXene) heterostructure was developed as the highly efficient electrochemiluminescence (ECL) functional material, which greatly improved the electrochemical properties and broadened the sensing application of MXenes. Gold single atoms were confined into the vacancy defects of Ti3C2Tx MXene, which could effectively avoid the masking of catalytic active sites. Meanwhile, electron transport could be accelerated with the assistance of titanium dioxide on the MXene nanosheets. Therefore, the AuSA/MXene heterostructure had high catalytic activity and electrical activity to promote hydrogen peroxide to generate free radicals, which achieved high-efficiency ECL. Eventually, the AuSA/MXene heterostructure was used to construct a Faraday cage-type ECL sensor with fluid nanoislands to detect miRNA-187 in triple-negative breast cancer tumor tissues.

A novel GSH-capping MXene QD-based ECL biosensor for the detection of miRNA221 in triple-negative breast cancer tumor

In this work, we have constructed a novel electrochemiluminescence (ECL) biosensor for the detection of miRNA221 based on glutathione-capped MXene-derived quantum dots (GSH-MQDs) and magnetic biomimic vesicles. Glutathione is used as precursor in the synthesis of MXene-derived QDs, which effectively improves the oxidation resistance of MXene. In the sensing system, GSH-MQDs still possess the advantages of MXene, including the excellent electrical conductivity and good electrochemical activity. The combination of the metal atoms on the MXene and the sulfhydryl group of GSH further reduce the defects in nanostructures of MXene-derived QDs. As a result, the stability and the luminescent properties of GSH-MQDs as ECL emitter have been significantly improved. Furthermore, magnetic biomimic vesicles are prepared as sensing platform to improve the feasibility and sensitivity for the miRNA221 detection. Moreover, a sensing strategy for miRNA221 detection is designed based on the cyclic amplification with T7 exonuclease. The biosensor is used to detect miRNA221 in the triple-negative breast cancer tumor tissues. The satisfactory results have indicated that this sensing strategy on the basis of GSH-MQD and magnetic biomimic vesicles possesses great potential for clinical analysis.

A Comprehensive Pan-Cancer Analysis of the Tumorigenic Role of Matrix Metallopeptidase 7 (MMP7) Across Human Cancers.

Growing evidence has shown the oncogenic function of matrix metallopeptidase 7 (MMP7) in various tumors. However, no systemic pan-cancer analysis on the association between MMP7 and different cancers based on big clinical data is available. TIMER2, GEPIA2, UALCAN, cBioPortal, String, Metascape, and other web databases were searched in the present study. Generally, MMP7 expression is significantly upregulated in most The Cancer Genome Atlas (TCGA) cancer types compared to the paired normal controls, yet is downregulated in tumor tissues of invasive breast carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and skin cutaneous melanoma (SKCM). MMP7 protein expression is notably higher in the primary tumor tissues of colon cancer, lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC) than in normal tissues and is significantly lower in the primary tumor tissues of breast cancer, clear cell renal carcinoma, and ovarian cancer. Furthermore, MMP7 expression is strongly associated with pathological stages, clinical outcomes, tumor mutational burden (TMB), and microsatellite instability (TSI). Gene amplification was detected in most TCGA cancer types. In addition, the missense mutation is the primary type of MMP7 genetic alteration in tumors. Significant positive correlations between MMP7 expression and cancer-associated fibroblasts (CAFs) have been demonstrated in most TCGA cancers. MMP7 expression was also found to be positively correlated with infiltration of dendritic cells and macrophages in some specific tumor types. Functional enrichment analysis by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO) methods revealed that RNA processing and DNA damage checkpoints might reveal the pathogenetic mechanisms of MMP7. This pan-cancer analysis provides a clear panorama for the tumorigenic roles of MMP7 across different cancer types. Moreover, MMP7 could be a potential drug therapeutic target in such cancers.

Abstract 5706: Epigenetic signatures in association with breast cancer mortality and prognosis that are specific to tumor subtype and menopausal status

Abstract Background: Despite advancements in screening and treatment options for breast cancer (BC), mortality from BC has increased, accounting for 15% of new cancer deaths in the U.S. in 2020. BC is heterogeneous cancer with different molecular subtypes defined by hormone-receptor status, and the prognoses of BC patients differ by their menopausal status in conjunction with their molecular subtypes. Epigenetic dysregulation patterns can serve as principal predictors of BC progression and mortality by capturing these differences in biology that are linked to BC outcomes, leading to personalized treatment plans. In this study, we aimed to detect subtype- or menopausal-specific DNA methylation (DNAm) in BC tumor tissues across the genome that are associated with BC progression or all-cause mortality. Methods: Associations between site-specific DNAm in tumor and BC survival were evaluated using the Illumina Infinium HumanMethylation450 BeadChip array data from the Cancer Genome Atlas participants. Cox proportional hazards models were used in the strata by tumor subtypes and menopausal status, adjusting for age, race, cancer stage, tumor purity, and cell type proportion. Detected site-specific DNAm was further analyzed to identify subtype- or menopausal-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset. Results: We identified eight CpG probes that were associated with survival outcomes in subtype- or menopausal-specific manner. Seven probes among women with luminal A subtype were associated with all-cause mortality or progression-free interval (PFI); four probes among women with luminal B were associated with PFI; and five probes among post-menopausal women were associated with PFI. Of them, six probes presented a lower risk of all-cause mortality or BC progression with higher DNAm. The identified DMRs differed by tumor subtype and menopausal status, and a majority of DMRs were driven by several weaker associations in the same direction among proximal loci. Also, we identified subtype- or menopausal-specific functional genomic pathways. Particularly, a pathway of insulin regulation was associated with all-cause mortality and PFI among pre-menopausal women. The detected site-specific probes were validated with consistent directions and magnitudes of effects on prognosis across two independent datasets. Conclusion: We identified subtype- or menopausal-specific DNAm in BC tumor tissues, DMRs, and functional pathways in association with all-cause mortality or BC progression. Our findings warrant future studies with larger independent datasets for replication and functional implications of detected DNAm. Our detected genome-wide-associated-CpG loci could improve prognosis prediction for BC patients, thus contributing to tailored therapeutic regimens. Citation Format: Do Hyun Kim, Alexandra M. Binder, Hua Zhou, Su Yon Jung. Epigenetic signatures in association with breast cancer mortality and prognosis that are specific to tumor subtype and menopausal status [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 5706.