Single-cell analysis of tumor microenvironment and cell adhesion reveals that interleukin-1 beta promotes cancer cell proliferation in breast cancer

Background: Triple-negative breast cancer(TNBC), which is so called because of the lack of estrogen receptors(ER), progesterone receptors(PR), and human epidermal growth factor receptor 2(HER2) receptors on the cancer cells, accounts for 10%–15% of all breast cancers. The heterogeneity of the tumor microenvironment is high.However, the role of plasma cells controlling the tumor migration progression in TNBC is still not fully understood.Methods: We analyzed single-cell RNA sequencing data from five HER2 positive, 12ER positive/PR positive, and nine TNBC samples. The potential targets were validated by immunohistochemistry.Results: Plasma cells were enriched in TNBC samples, which was consistent with validation using data from The Cancer Genome Atlas. Cell communication analysis revealed that plasma cells interact with T cells through the intercellular adhesion molecule 2–integrin–aLb2 complex, and then release interleukin 1 beta(IL1B), as verified by immunohistochemistry, ultimately promoting tumor growth.Conclusion: Our results revealed the role of plasma cells in TNBC and identified IL1B as a new prognostic marker for TNBC.

Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Bibliometric analysis of phosphoglycerate kinase 1 expression in breast cancer and its distinct upregulation in triple-negative breast cancer

BACKGROUND Phosphoglycerate kinase 1(PGK1)has been identified as a possible biomarker for breast cancer(BC)and may play a role in the development and advancement of triple-negative BC(TNBC).AIM To explore the PGK1 and BC research status and PGK1 expression and mecha-nism differences among TNBC,non-TNBC,and normal breast tissue.METHODS PGK1 and BC related literature was downloaded from Web of Science Core Co-llection Core Collection.Publication counts,key-word frequency,cooperation networks,and theme trends were analyzed.Normal breast,TNBC,and non-TNBC mRNA data were gathered,and differentially expressed genes obtained.Area under the summary receiver operating characteristic curves,sensitivity and specificity of PGK1 expression were determined.Kaplan Meier revealed PGK1’s prognostic implication.PGK1 co-expressed genes were explored,and Gene Onto-logy,Kyoto Encyclopedia of Genes and Genomes,and Disease Ontology applied.Protein-protein interaction networks were constructed.Hub genes identified.RESULTS PGK1 and BC related publications have surged since 2020,with China leading the way.The most frequent keyword was“Expression”.Collaborative networks were found among co-citations,countries,institutions,and authors.PGK1 expression and BC progression were research hotspots,and PGK1 expression and BC survival were research frontiers.In 16 TNBC vs non-cancerous breast and 15 TNBC vs non-TNBC datasets,PGK1 mRNA levels were higher in 1159 TNBC than 1205 non-cancerous breast cases[standardized mean differences(SMD):0.85,95%confidence interval(95%CI):0.54-1.16,I²=86%,P<0.001].PGK1 expression was higher in 1520 TNBC than 7072 non-TNBC cases(SMD:0.25,95%CI:0.03-0.47,I²=91%,P=0.02).Recurrence free survival was lower in PGK1-high-expression than PGK1-low-expression group(hazard ratio:1.282,P=0.023).PGK1 co-expressed genes were concentrated in ATP metabolic process,HIF-1 signaling,and glycolysis/gluconeogenesis pathways.CONCLUSION PGK1 expression is a research hotspot and frontier direction in the BC field.PGK1 may play a strong role in promoting cancer in TNBC by mediating metabolism and HIF-1 signaling pathways.

Molecular Docking Studies of Botanical Beverage Mix Berries (LIFEGREENTM) against Breast Cancer Cells from Targeted Protein 1QQG, 7B5Q & 7B5O & Uterine Fibroid from Targeted Protein 2AYR, 6T41 & 3GRF

Fibroids, also called leiomyomas or myomas, are communal tumors of the muscle or uterine wall that affect about 20% of females who are of reproductive age. They can look as if singly or in clusters, and they often cease to grow after menopause. Fibroids can be classified as intramural, sub serosal, pedunculated, or submucosal based on where they are positioned in the uterus. Although fibroids are benign, they can grow quickly and cause a range of symptoms, such as pelvic pressure, heavy menstrual flow, and infertility. As a result, fibroids are a main reason behind hysterectomy surgeries. The majority of cases of breast cancer are ductal and lobular cancers, making it the second utmost common cancer in women international. Gene mutations like those in BRCA1 or BRCA2 knowingly raise the risk of breast and other cancers, typically with an earlier cancer onset. Cancer risk is influenced by a complex interplay of genetic abnormalities, environmental factors, and lifestyle selections. Further research into these relations is domineering. Although they are common in uterine leiomyomas, especially multiple leiomyomas, MED12 mutations do not significantly correlate with tumor size. These mutations have also been noticed in smooth muscle tumors and leiomyosarcomas, two other types of uterine cancer. The identification of MED12 mutations as the sole genetic abnormality originates in leiomyomas raises the opportunity of a role in the genesis of cancer. 10% - 15% of women who are of reproductive age have endometriosis, which grants serious difficulties because of its chronic nature and range of clinical symptoms. Even after effective surgeries, issues reoccur often, adding to the enormous financial burden. The effects of MED12 mutations have been experiential in recent studies examining the molecular causes of endometriosis-associated infertility, which have shown anomalies in cellular connections and signaling cascades. Computational techniques were used in this study to investigate LifeGreenTM’s potential to prevent uterine fibroids and breast cancer. The efficacy of LifeGreenTM as a preventive measure or a treatment for common gynecological matters was examined and modeled. We investigated the mechanisms underlying LifeGreenTM’s benefits in the treatment of uterine fibroids and breast cancer using computational techniques. Our research contributes to our understanding of its potential therapeutic benefits for women’s health.

Expression and Prognostic Potential of ESR1 in Breast Cancer

This study aims to explore the potential of ESR1 as a biomarker in breast cancer(BRCA)using bioinformatics analysis tools.The up-regulation of ESR1 expression in BRCA was investigated using UALCAN and GEPIA2,illustrating its role in BRCA progression.Furthermore,analyses based on various variables such as gender,age,race,and pathological stages of BRCA patients revealed a consistent up-regulation of ESR1,emphasizing its role in the development and progression of BRCA.Additionally,an analysis of ESR1 promoter methylation levels across various parameters revealed hypomethylation,affirming the inverse correlation between methylation and ESR1 expression.Prognostic analysis further indicated that overexpression of ESR1 is associated with poor overall survival,highlighting its potential as a prognostic biomarker in BRCA.Moreover,genetic mutation analysis using cBioPortal disclosed a minor role of ESR1 genetic mutations in BRCA,with only 2.5%of genetic alterations observed.The STRING and DAVID tools were utilized to conduct pathway enrichment analysis,revealing diverse biological functions of ESR1 and its 10 interconnected genes.Altogether,these results underscore the significance of understanding ESR1 up-regulation in BRCA and demonstrate its potential as a therapeutic,diagnostic,and prognostic biomarker.

Predicting the Prognosis and Immunotherapeutic Response of Triple-Negative Breast Cancer by Constructing a Prognostic Model Based on CD8+T Cell-Related Immune Genes

Objective Triple-negative breast cancer(TNBC)poses a significant challenge for treatment efficacy.CD8+T cells,which are pivotal immune cells,can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology.By leveraging these genes,our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy.Methods Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases.In the initial stage,we identified 67 differentially expressed genes associated with immune response in CD8+T cells.Subsequently,we narrowed our focus to three key genes,namely CXCL13,GBP2,and GZMB,which were used to construct a prognostic model.The accuracy of the model was assessed using the validation set data and receiver operating characteristic(ROC)curves.Furthermore,we employed various methods,including Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway,immune infiltration,and correlation analyses with CD274(PD-L1)to explore the model's predictive efficacy in immunotherapeutic responses.Additionally,we investigated the potential underlying biological pathways that contribute to divergent treatment responses.Results We successfully developed a model capable of predicting the prognosis of patients with TNBC.The areas under the curve(AUC)values for the 1-,3-,and 5-year survival predictions were 0.618,0.652,and 0.826,respectively.Employing this risk model,we stratified the samples into high-and low-risk groups.Through KEGG enrichment analysis,we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism,whereas the low-risk group demonstrated significant enrichment in cytokine pathways.Furthermore,immune landscape analysis revealed noteworthy variations between(PD-L1)expression and risk scores,indicating that our model effectively predicted the response of patients to immune-based treatments.Conclusion Our study demonstrates the potential of CXCL13,GBP2,and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC.These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.

Germline pathogenic variants among high hereditary risk patients with breast and ovarian cancer and unaffected subjects in Lebanese Arab women

BACKGROUND The prevalence of germline pathogenic variants in high hereditary risk breast and/or ovarian cancer patients and unaffected subjects referred for testing is an unmet need in low and middle-income countries.AIM To determine the prevalence of germline pathogenic variants in high hereditary risk patients with breast and/or ovarian cancer and unaffected individuals.METHODS We retrospectively reviewed records of patients and unaffected subjects referred for germline pathogenic variant testing due to high hereditary risk between 2010-2020.Data was collected and analyzed on Excel sheet.RESULTS In total,358 individuals were included,including 257 patients and 101 unaffected individuals with relatives with breast or ovarian cancer.The prevalence of breast cancer susceptibility gene(BRCA)1/2 pathogenic variants was 8.63%(19/220)in patients with breast cancer,and 15.1%(5/33)in those with ovarian cancer.Among the 25 of 220 patients with breast cancer tested by next-generation sequencing,3 patients had pathogenic variants other than BRCA1/2.The highest risk was observed in those aged 40 years with breast cancer and a positive family history,where the BRCA1/2 prevalence was 20.1%(9/43).Among the unaffected subjects,31.1%(14/45)had the same BRCA1/2 pathogenic variants in their corresponding relatives.Among the subjects referred because of a positive family history of cancer without known hereditary factors,5.35%(3/56)had pathogenic variants of BRCA1 and BRCA2.The c.131G>T nucleotide change was noted in one patient and two unrelated unaffected subjects with a BRCA1 pathogenic variant.CONCLUSION This study showed a 8.63%prevalence of pathogenic variants in patients with breast cancer and a 15.1%prevalence in patients with ovarian cancer.Among the relatives of patients with BRCA1/2 pathogenic variants,31%tested positive for the same variant,while 5.3%of subjects who tested positive due to a family history of breast cancer had a BRCA pathogenic variant.

TMED2 Induces Cisplatin Resistance in Breast Cancer via Targeting the KEAP1-Nrf2 Pathway

Objective Cisplatin is the first-line treatment for breast cancer,but it faces challenges of drug resistance.This study investigated new molecular mechanisms underlying cisplatin resistance in breast cancer.Methods We analyzed sequencing data from the TCGA database to identify potential associations between transmembrane emp24 protein transport domain containing 2(TMED2)and breast cancer.Western blotting,real-time PCR,CCK-8,and TUNEL assays were used to measure the effects and molecular mechanism of TMED2 on cisplatin resistance in MCF-7 and MDA-MB-231 cell lines.Results TMED2 was overexpressed in breast cancer and associated with poor prognosis.TMED2 increased cisplatin resistance in breast cancer cells in vitro via promoting ubiquitination of Kelch-like ECH-associated protein 1(KEAP1),relieving inhibition of KEAP1 on nuclear factor erythroid 2-related factor 2(Nrf2),and increasing expression of downstream drug resistance related genes,such as heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion We identified a new molecular mechanism by which TMED2 affects cisplatin resistance in breast cancer.Our results provide theoretical guidance for future clinical applications.

Cancer risk in relatives of BRCA1/2 pathogenic variant carriers in a large series of unselected patients with breast cancer

Objective:The spectrum and risk of cancer in relatives of BRCA1/2 pathogenic variant carriers in the Chinese population have not been established.Methods:A family history of cancer in 9903 unselected breast cancer patients was retrospectively analyzed.BRCA1/2 status was determined for all patients and relative risks(RRs)were calculated to evaluate cancer risk in relatives of the patients.Results:The incidences of breast cancer in female relatives of BRCA1 carriers,BRCA2 carriers,and non-carriers were 33.0%,32.2%,and 7.7%,respectively.The corresponding incidences of ovarian cancer were 11.5%,2.4%,and 0.5%,respectively.The incidences of pancreatic cancer in male relatives of BRCA1 carriers,BRCA2 carriers,and non-carriers were 1.4%,2.7%,and 0.6%,respectively.The corresponding incidences of prostate cancer were 1.0%,2.1%,and 0.4%,respectively.The risks of breast and ovarian cancers in female relatives of BRCA1 and BRCA2 carriers were significantly higher than female relatives of non-carriers(BRCA1:RR=4.29,P<0.001 and RR=21.95,P<0.001;BRCA2:RR=4.19,P<0.001 and RR=4.65,P<0.001,respectively).Additionally,higher risks of pancreatic and prostate cancers were noted in male relatives of BRCA2 carriers than non-carriers(RR=4.34,P=0.001 and RR=4.86,P=0.001,respectively).Conclusions:Female relatives of BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers,and male relatives of BRCA2 carriers are at increased risk for pancreatic and prostate cancers.

MiR-19a-3p/PTEN axis regulates the anticancer effect of circHIAT1in breast cancer in vitro

Objective: Breast cancer is a major cancer threatening the health of women globally. To elucidate the effect ofthe circHIAT1/miR-19a-3p/phosphatase and tensin homolog (PTEN) axis on regulating the malignant phenotype ofbreast cancer cells. Methods: The mRNA expression pattern of circHIAT1, miR-19a-3p, and PTEN was checked byreal-time quantitative polymerase chain reaction. Then, the knockdown assay was carried out to explore the effect ofcircHIAT1 and miR-19a-3p on breast cancer. The relative cell experiments, including MTT assay, scratch assay,transwell invasion assay, and flow cytometry analysis, were conducted to verify the influence of circHIAT1 and miR-19a-3p on breast cancer cells. Results: The levels of PTEN and circHIAT1 were reduced, while that of miR-19a-3pwas elevated in breast cancer tissues and cells. MiR-19a-3p was proved to be the target gene of circHIAT1 via a dualluciferase experiment, which could also modulate the PTEN mRNA level. Overexpression of circHIAT1 was able toundermine the growth, migratory ability, and invasiveness in breast cancer cells, which could be antagonized by miR-19a-3p mimic. The inhibition of miR-19a-3p in vitro also impaired the malignancy of breast cancer, which dependedon the modulation of PTEN expression. Conclusion: CircHIAT1 controls the PTEN expression level in cells of breastcancer by negatively regulating miR-19a-3p. This mechanism controls the growth, invasion, and migration of breastcancer.

Deleted in liver cancer 1 suppresses the growth of prostate cancer cells through inhibiting Rho-associated protein kinase pathway

Objective:Deleted in liver cancer 1(DLC1)is a GTPase-activating protein that is reported as a suppressor in certain human cancers.However,the detailed biological function of DLC1 is still unclear in human prostate cancer(PCa).In the present study,we aimed to explore the function of DLC1 in PCa cells.Methods:Silencing and overexpression of DLC1 were induced in an androgen-sensitive PCa cell line(LNCaP)using RNA interference and lentiviral vector transduction.The Cell Counting Kit-8 assay was performed to determine cell proliferation.The cell cycle was examined by performing a propidium iodide staining assay.Results:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of LNCaP cells.Moreover,DLC1 expression was negatively correlated with Rho-associated protein kinase(ROCK)expression in LNCaP cells.Importantly,this study showed that the ROCK inhibitor Y27632 restored the function of DLC1 in LNCaP cells and reduced the tumorigenicity of LNCaP cells in vivo.Conclusion:Our results indicated that DLC1 overexpression markedly suppressed the proliferation and cell cycle progression of PCa cells and negatively correlated with ROCK expression in PCa cells and tissue.

Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer

Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.

High expression of autophagy-related gene EIF4EBP1 could promote tamoxifen resistance and predict poor prognosis in breast cancer

BACKGROUND Breast cancer(BC) remains a public health problem. Tamoxifen(TAM) resistance has caused great difficulties for treatment of BC patients. Eukaryotic translation initiation factor 4E binding protein 1(EIF4EBP1) plays critical roles in the tumorigenesis and progression of BC. However, the expression and mechanism of EIF4EBP1 in determining the efficacy of TAM therapy in BC patients are still unclear.AIM To investigate the expression and functions of EIF4EBP1 in determining the efficacy of TAM therapy in BC patients.METHODS High-throughput sequencing data of breast tumors were downloaded from the Gene Expression Omnibus database. Differential gene expression analysis identified EIF4EBP1 to be significantly upregulated in cancer tissues. Its prognostic value was analyzed. The biological function and related pathways of EIF4EBP1 was analyzed. Subsequently, the expression of EIF4EBP1 was determined by real-time reverse transcription polymerase chain reaction and western blotting. Cell Counting Kit-8 assays, colony formation assay and wound healing assay were used to understand the phenotypes of function of EIF4EBP1.RESULTS EIF4EBP1 was upregulated in the TAM-resistant cells, and EIF4EBP1 was related to the prognosis of BC patients. Gene Set Enrichment Analysis showed that EIF4EBP1 might be involved in Hedgehog signaling pathways. Decreasing the expression of EIF4EBP1 could reverse TAM resistance, whereas overexpression of EIF4EBP1 promoted TAM resistance.CONCLUSION This study indicated that EIF4EBP1 was overexpressed in the BC and TAM-resistant cell line, which increased cell proliferation, invasion, migration and TAM resistance in BC cells.

IL-35、Beclin-1在乳腺癌患者外周血中的水平及意义

目的探讨白细胞介素(IL)-35、自噬相关蛋白Beclin-1在乳腺癌患者外周血中的水平及意义。方法选取2022年5-10月在上海市嘉定区妇幼保健院诊治的原发性乳腺癌女性患者44例(乳腺癌组)、乳腺良性肿瘤女性患者40例(乳腺良性肿瘤组)及体检的健康者40例(健康对照组)作为研究对象。采用酶联免疫吸附试验检测并比较各组外周血中IL-35和Beclin-1水平,同时检测乳腺癌患者糖类抗原15-3(CA15-3),比较不同临床病理特征的乳腺癌患者IL-35、Beclin-1、CA15-3水平;分析乳腺癌患者外周血IL-35、Beclin-1、CA15-3水平之间的相关性。结果乳腺癌组和乳腺良性肿瘤组外周血IL-35水平均高于健康对照组(P<0.05),Beclin-1水平均低于健康对照组(P<0.05)。乳腺癌组外周血IL-35水平高于乳腺良性肿瘤组(P<0.05),Beclin-1水平低于乳腺良性肿瘤组(P<0.05)。不同病理分级、淋巴结转移情况的乳腺癌患者外周血IL-35、Beclin-1水平比较,差异均有统计学意义(P<0.05);不同雌激素受体(ER)检测结果的乳腺癌患者外周血IL-35水平比较,差异无统计学意义(P>0.05),而Beclin-1水平比较,差异有统计学意义(P<0.05)。乳腺癌患者外周血IL-35水平与Beclin-1水平呈负相关(r=-0.484,P<0.05);IL-35、Beclin-1水平与CA15-3水平均无相关性(均P>0.05)。结论乳腺癌患者外周血IL-35水平升高、Beclin-1水平降低。不同病理分级、淋巴结转移情况的乳腺癌患者外周血IL-35、Beclin-1水平有明显差异。乳腺癌患者外周血IL-35水平与Beclin-1水平呈负相关,而IL-35、Beclin-1水平与肿瘤标志物CA15-3水平均无关。

多排螺旋CT检测联合血清GLP-1、PINP对乳腺癌术后骨质疏松症的诊断价值

目的 探究多排螺旋CT检测联合血清胰高血糖素样肽1(GLP-1)、Ⅰ型前胶原氨基端前肽(PINP)对乳腺癌术后骨质疏松症的诊断价值。方法选取2021年1月至2023年1月本院就诊的152例乳腺癌手术史的患者,根据术后双能X线检测是否出现骨质疏松分为骨质疏松组(62例)和非骨质疏松组(90例);患者均进行多螺旋CT以及双能X线检测;酶联免疫吸附法检测血清GLP-1、PINP水平;受试者工作特征(ROC)曲线分析血清GLP-1、PINP对乳腺癌术后骨质疏松症的临界诊断点;采用四格表分析多排螺旋CT联合血清GLP-1、PINP对乳腺癌术后骨质疏松症的诊断价值。结果骨质疏松组CT值显著低于非骨质疏松组(P<0.05)。骨质疏松组血清GLP-1水平显著低于非骨质疏松组(P<0.05),PINP水平显著高于非骨质疏松组(P<0.05)。血清GLP-1诊断乳腺癌术后骨质疏松症的曲线下面积(AUC)为0.842,血清PINP诊断乳腺癌术后骨质疏松症的AUC为0.881,CT值诊断乳腺癌术后骨质疏松症的AUC为0.889,三者联合诊断乳腺癌术后骨质疏松症的AUC为0.971。多排螺旋CT在乳腺癌术后骨质疏松症诊断中准确度为89.47%,灵敏度为91.11%,特异度为87.10%;GLP-1在乳腺癌术后骨质疏松症诊断中准确度为84.87%,灵敏度为87.78%,特异度为80.65%;PINP在乳腺癌术后骨质疏松症诊断中准确度为82.89%,灵敏度为85.56%,特异度为79.03%;三者联合检测在乳腺癌术后骨质疏松症诊断中准确度为93.42%,灵敏度为94.44%,特异度为91.94%。结论血清GLP-1水平降低,PINP水平升高与乳腺癌术后骨质疏松症发生有关,多排螺旋CT联合血清GLP-1、PINP可提高乳腺癌术后骨质疏松症的诊断价值。

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients

BACKGROUND Poly(ADP-ribose)polymerase inhibitors(PARPis)are approved as first-line therapies for breast cancer gene(BRCA)-positive,human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer.They are also effective for new and recurrent ovarian cancers that are BRCA-or homologous recombination deficiency(HRD)-positive.However,data on these mutations and PARPi use in the Middle East are limited.AIM To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.METHODS This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations,and 25 of 65 ovarian cancer patients tested for HRD.These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023.Data were summarized using descriptive statistics and compared using counts and percentages.Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.RESULTS Among the 472 breast cancer patients,12.1%underwent BRCA testing,and 38.5%of 65 ovarian cancer patients received HRD testing.Pathogenic mutations were found in 25.6%of the tested patients:26.3%breast cancers had germline BRCA(gBRCA)mutations and 24.0%ovarian cancers showed HRD.Notably,40.0%of gBRCA-positive breast cancers and 66.0%of HRD-positive ovarian cancers were Middle Eastern and Asian patients,respectively.PARPi treatment was used in 5(33.3%)gBRCA-positive breast cancer patients as first-line therapy(n=1;7-months progression-free),for maintenance(n=2;>15-months progression-free),or at later stages due to compliance issues(n=2).Four patients(66.6%)with HRD-positive ovarian cancer received PARPi and all remained progression-free.CONCLUSION Lower testing rates but higher BRCA mutations in breast cancer were found.Ethnicity reflected United Arab Emirates demographics,with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

不同临床病理特征卵巢浆液性肿瘤患者E-cadherin、BRCA1及P53的表达变化研究

目的:探究不同卵巢浆液性肿瘤中E-钙黏蛋白(E-cadherin)、乳腺癌易感基因1(BRCA1)、P53的表达变化情况。方法:选取2017年12月—2022年2月赣州市妇幼保健院的50例卵巢浆液性癌患者为A组,同时期的40例卵巢交界性浆液性肿瘤患者为B组,30例卵巢良性浆液性囊腺瘤患者为C组。检测及比较三组的组织E-cadherin、BRCA1、P53表达情况,并比较A组中不同年龄、淋巴结转移情况、FIGO分期及不同病理分级者的检测结果。结果:A组的E-cadherin及BRCA1阳性率显著均低于B组及C组,B组则显著均低于C组(P<0.05);A组P53阳性率显著高于B组及C组,B组则显著高于C组(P<0.05)。A组中低级别浆液性癌者E-cadherin和BRCA1阳性率均高于高级别浆液性癌者,低级别浆液性癌者P53阳性率显著低于高级别浆液性癌者,差异均有统计学意义(P<0.05)。A组中不同年龄及FIGO分期者的组织E-cadherin、BRCA1及P53阳性率比较,差异均无统计学意义(P>0.05)。A组有淋巴结转移者E-cadherin和BRCA1阳性率均低于无淋巴结转移者,有淋巴结转移者P53阳性率高于无淋巴结转移者,差异均有统计学意义(P<0.05)。结论:卵巢浆液性癌患者中E-cadherin及BRCA1呈低表达,而P53呈高表达,且不同临床病理情况者存在差异,因此在卵巢浆液性癌的早期筛查检测中有一定的参考价值。

超声测定PI、RI、Vmax结合血清sE-cadherin、CYFRA21-1对乳腺癌良恶性及淋巴结转移的诊断价值

目的研究超声测定的搏动指数(PI)、血流阻力指数(RI)、最大血流值(Vmax)结合血清可溶性E-钙黏连蛋白(sE-cadherin)、细胞角蛋白19片段(CYFRA21-1)对乳腺癌良恶性及腋窝淋巴结转移的诊断价值。方法选择242例乳腺肿块女性患者,年龄43~67岁,平均年龄55.23岁;身体质量指数19.5~28.9 kg/m^(2),平均身体质量指数24.12 kg/m^(2);病程4~8个月,平均病程6.45个月;均为初次入院就诊。彩色多普勒超声仪测定PI、RI和Vmax,并在术前采集空腹外周血,酶联免疫吸附分析测定血清sE-cadherin和CYFRA21-1。根据病理组织诊断结果将患者分成乳腺癌组(n=132)和乳腺良性组(n=110),并将乳腺癌患者分成腋窝淋巴结转移组(n=74)和腋窝淋巴结未转移组(n=58)。单因素分析临床资料,Logistic回归分析乳腺癌发生和腋窝淋巴结转移的独立影响因素,通过受试者工作特性(ROC)曲线分析各指标及回归分析诊断效能。结果乳腺良恶性病变区分ROC曲线结果表明,PI临界值1.34,灵敏度为69.70%,特异度为70.91%,曲线下面积(AUC)为0.801[95%可信区间(CI)0.750~0.852];RI诊断的临界值为0.69,灵敏度为65.15%,特异度65.45%,AUC为0.762(95%CI 0.707~0.812);Vmax诊断的临界值为13.11 m/s,灵敏度为59.85%,特异度60.00%,AUC为0.627(95%CI 0.564~0.699);血清sE-cadherin诊断的临界值为24.18 ng/mL,灵敏度为62.88%,特异度58.18%,AUC为0.709(95%CI 0.645~0.771);血清CYFRA21-1诊断的临界值为9.55 g/mL,灵敏度为74.24%,特异度75.45%,AUC为0.817(95%CI 0.769~0.865)。将回归预测方程作为新变量P,在最佳临界切点时,回归分析灵敏度81.82%,特异度79.09%,AUC为0.867(95%CI 0.829~0.908),回归分析灵敏度显著高于各指标单独检测(P<0.05)。乳腺癌淋巴结转移分析ROC曲线结果表明,PI临界值1.58,灵敏度为79.73%,特异度为68.97%,AUC为0.815(95%CI 0.727~0.902);RI诊断的临界值为0.83,灵敏度为63.51%,特异度70.69%,AUC为0.701(95%CI 0.558~0.844);Vmax诊断的临界值为17.36 m/s,灵敏度为54.05%,特异度55.17%,AUC为0.516(95%CI 0.384~0.649);血清sE-cadherin诊断的临界值为34.52 ng/mL,灵敏度为82.43%,特异度60.34%,AUC为0.755(95%CI 0.653~0.856);血清CYFRA21-1诊断的临界值为13.10 g/mL,灵敏度为60.81%,特异度65.52%,AUC为0.563(95%CI 0.426~0.701)。将回归预测方程作为新变量P,在最佳临界切点时,回归分析灵敏度85.14%,特异度84.48%,AUC为0.893(95%CI 0.816~0.970),回归分析灵敏度显著高于各指标单独检测(P<0.05)。结论超声参数及血清sE-cadherin和CYFRA21-1在乳腺癌和腋窝淋巴结中异常表达,且PI、RI、Vmax和血清sE-cadherin、CYFRA21-1单独和Logistic回归分析可应用于乳腺恶性病变和淋巴结转移的预测和诊断。

BMP-6 inhibits microRNA-21 expression in breast cancer through repressing 6EF1 and AP-1

MicroRNAs （miRNAs）, which are small noncoding RNA molecules, play important roles in the post-transcriptional regulation process. The microRNA-21 gene （miR-21） has been reported to be highly expressed in various solid tumors, including breast cancer. Bone morphogenetic protein-6 （BMP-6） has been identified as an inhibitor of breast cancer epithelial-mesenchymal transition （EMT） through rescuing E-cadherin expression. We initiated experi- ments to identify the relationships between miR-21 and BMP-6 in breast cancer progression. Real-time PCR analysis showed that miR-21 expression was very high in MDA-MB-231 cells that expressed little BMP-6. A reverse correla- tion between BMP-6 and miR-21 was also determined in breast cancer tissue samples. Moreover, BMP-6 inhibited miR-21 transcription in MDA-MB-231 cells. In order to investigate how BMP-6 inhibited the miR-21 promoter （miPPR-21）, we constructed a series of miPPR-21 reporters. Luciferase assay results indicated that BMP-6 inhibited miPPR-21 activity through the E2-box and AP-l-binding sites. We also demonstrated that both δEF1 and TPA in- duced miR-21 expression. Using site-directed mutation and CHIP assay, we found that δEF1 induced miPPR-21 ac- tivity by binding to the E2-box on miPPR-21. Moreover, TPA triggered miPPR-21 activity through the AP-I binding sites. BMP-6 treatment significantly reduced the binding of these factors to miPPR-21 by decreasing the expression of δEF1 and c-Fos/c-Jun. We also demonstrated that BMP-6-induced downregulation of miR-21 modified the activ- ity of PDCD4 3＇UTR and inhibited MDA-MB-231 cell invasion. δEF1 overexpression and TPA induction blocked this inhibitory effect of BMP-6. In conclusion, BMP-6-induced inhibition of miR-21 suggests that BMP-6 may function as an anti-metastasis factor by a mechanism involving transcriptional repression of miR-21 in breast cancer.

Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer in vitro and in vivo

OBJECTIVE To discover a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and exploreits potential mechanisms.METHODS ULK1 expression was analyzed by The Cancer Genome Atlas(TCGA)analysis and tissue microarray(TMA)analysis.ULK1agonist was designed by using in silico screening,as well as modified by chemical synthesis and screened by kinase and anti-proliferative activities.The amino acid residues that key to the activation site of LYN-1604 were determined by site-directed mutagenesis,as well as in vitro kinase assay and ADP-Glo kinase assay.The mechanisms of LYN-1604 induced cell death were investigated by fluorescence microscope,western blotting,flow cytometry analysis,immunocytochemistry,as well as si RNA and GFP-m RFP-LC3 plasmid transfections.Potential ULK1 interactors were discovered by performing comparative microarray analysis and the therapeutic effect of LYN-1604 was assessed by xenograft breast cancer mouse model.RESULTS We found that ULK1 was remarkably downregulated in breast cancer tissue samples,especial y in triple negative breast cancer(TNBC).32 candidate smal molecules were synthesized,and we discovered a small molecule named LYN-1604 as the best candidate ULK1agonist.Additionally,we identified that three amino acid residues(LYS50,LEU53 and TYR89)were key to the activation site of LYN-1604 and ULK1.Subsequently,we demonstrated that LYN-1604 could induce autophagy-associated cell death via ULK complex(ULK1-m ATG13-FIP200-ATG101)in MDA-MB-231 cells.We also found that LYN-1604 induced cell death involved in ATF3,RAD21 and caspase 3,accompanied with autophagy and apoptosis.Moreover,we demonstrated that LYN-1604 had a good therapeutic potential on TNBC by targeting ULK1-modulated cell death in vivo.CONCLUSION We discovered a small molecule(LYN-1604)has therapeutic potential by targeting ULK1-modulated cell death associated with autophagy and apoptosis of TNBC in vitro and in vivo,which could be utilized as a new anti-TNBC drug candidate.