Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, ...Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.展开更多
Background:A positive association between the ABO blood types and survival has been suggested in several malignancies.The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of ...Background:A positive association between the ABO blood types and survival has been suggested in several malignancies.The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of Chinese patients with curatively resected non-small cell lung cancer(NSCLC).Methods:We retrospectively analyzed 1601 consecutive Chinese patients who underwent curative surgery for NSCLC between January 1,2005 and December 31,2009.The relationship between the ABO blood types and survival was investigated.In addition,univariate and multivariate analyses were performed.Results:Group 1(patients with the blood type O or B) had significantly prolonged overall survival(OS) compared with group 2(patients with the blood type A or AB),with a median OS of 74.9 months versus 61.5 months[hazard ratio(HR) 0.83;95%confidence interval(CI) 0.72-0.96;P = 0.015].Additionally,group 1 had significantly longer disease-free survival(DFS;HR 0.86;95%CI 0.76-0.98;P = 0.022) and locoregional relapse-free survival(LRFS;HR 0.79;95%CI 0.64-0.98;P = 0.024) than group 2.The association was not significantly modified by other risk factors for NSCLC,including smoking status,pathologic tumor-node-metastasis stage,pT category,pN category,and chemotherapy.Conclusions:There is an association between the ABO blood types and the survival of Chinese patients with resected NSCLC.Patients with the blood type O or B had significantly prolonged OS,DFS,and LRFS compared with those with the blood type A or AB.展开更多
Ubiquitin-conjugating enzyme 9(Ubc9),the sole conjugating enzyme for sumoylation,regulates protein function and plays an important role in tumorigenesis.Whether Ubc9 is involved in the chemoresistance of breast cancer...Ubiquitin-conjugating enzyme 9(Ubc9),the sole conjugating enzyme for sumoylation,regulates protein function and plays an important role in tumorigenesis.Whether Ubc9 is involved in the chemoresistance of breast cancer remains unknown.In this study,we aimed to evaluate the contribution of Ubc9 in the chemoresistance of breast cancer.Immunohistochemistry(IHC) was used to examine the expression level of Ubc9.Chi-square test,Wilcoxon test,and one-way ANOVA were applied to analyze the relationship between Ubc9 expression,clinicopathologic features,and clinical response to neoadjuvant chemotherapy.The significance of variables for survival was analyzed by the Cox proportional hazards model in a multivariate analysis.Kaplan-Meier survival curves were plotted and log-rank test was performed.The proportion of Ubc9-positive cells was higher in invasive ductal carcinoma than in normal breast tissues [(48.48 ± 17.94)% vs.(5.82 ± 2.80)%,P < 0.001].High Ubc9 expression was associated with poor differentiation(χ2 = 6.538,P = 0.038),larger tumor size(χ2 = 4.701,P = 0.030),advanced clinical stage(χ2 = 4.651,P = 0.031),lymph node metastasis(χ2 = 9.913,P = 0.010),basal-like phenotype(χ2 = 8.660,P = 0.034),and poor clinical response to neoadjuvant chemotherapy(χ2 = 11.09,P = 0.001).The expected 6-year cumulative disease-free survival rate was 87.32% in patients with low Ubc9 expression compared to 68.78% in those with high Ubc9 expression(χ2 = 4.289,P = 0.038).These data indicate that high Ubc9 expression correlates with poor response to chemotherapy and poor clinical prognosis.展开更多
Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mec...Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression,and to identify a novel prognosis marker and treatment target of breast malignant PTs.Methods The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing(scRNA-seq),immunostaining,real-time PCR and other methodologies.Functional experiments including proliferation assay,colony formation assay,transwell assay,and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs.The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft(PDX)model.Transcriptome sequencing,proteomic analysis,co-immunoprecipitation,and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism.Results In this study,the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in theα-SMA+fibroblast subset.Furthermore,a progressive elevation in the level of CD146 was observed with the malignant progression of PTs.More importantly,CD146 was found to serve as an independent predictor for recurrence in PT patients.Furthermore,CD146 was found to augment the viability and invasion of PTs.Mechanistically,CD146 acted as a protective“shield”to prevent the degradation of Discoidin,CUB,and LCCL domain-containing protein 2(DCBLD2),thereby activating the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and enhancing malignant behaviors of PT cells.In the malignant PT organoid and PDX model,a significant suppression of malignant PT growth was observed after the application of AA98.Conclusions These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs.The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.展开更多
Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptot...Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptotic extracellular vesicles(apoEVs)are inevitably phagocytosed by live tumor cells,promoting tumor heterogeneity.Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence.Herein,we conducted a series of in vivo and in vitro experiments,and we report that tumor-derived apoEVs promoted lung adenocarcinoma(LUAD)metastasis,self-renewal and chemoresistance.Mechanistically,we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2.In addition,we found that ALDH1A1,which was transported by apoEVs,activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells.Furthermore,targeting apoEVs-ALDH1A1 significantly abrogated these effects.Collectively,our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations,and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.展开更多
Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear...Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.展开更多
Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely...Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely unexplored.In this study,microarray was leveraged for the first time to investigate the role of lncRNA in PT.We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT,and its overexpression endowed PT with high tumor grade and adverse prognosis.Furthermore,we elucidated that ZFPM2-AS1 promotes the proliferation,migration,and invasion of malignant PT in vitro.Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft(PDX)model could effectively inhibit tumor progression in vivo.Mechanistically,our findings showed that ZFPM2-AS1 is competitively bound to CDC42,inhibiting ACK1 and STAT1 activation,thereby launching the transcription of TNFRSF19.In conclusion,our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT,and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.展开更多
基金supported by the National Natural Science Foundation of China (No. 82003311, No. 82061148016, No. 82230057 and No. 82272859)National Key R&D Program of China (No. 2022YFC2505101)+2 种基金Sun Yat-Sen Clinical Research Cultivating Program (No. SYS-Q202004)Beijing Medical Award Foundation (No. YXJL2020-0941-0760)Guangzhou Science and Technology Program (No. 202102010272 and No. 202201020486)。
文摘Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin(PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2(HER2)-positive early breast cancer(BC).Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD(30-35 mg/m^(2)) and cyclophosphamide(600 mg/m^(2)), followed by four cycles of taxanes(docetaxel,90-100 mg/m^(2) or nab-paclitaxel, 260 mg/m^(2)), concomitant with eight cycles of trastuzumab(8 mg/kg loading dose,then 6 mg/kg) and pertuzumab(840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response(tp CR, yp T0/is yp N0). Secondary endpoints included breast p CR(bp CR),objective response rate(ORR), disease control rate, rate of breast-conserving surgery(BCS), and safety(with a focus on cardiotoxicity).Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42(53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval(95% CI), 48.5%-71.2%] patients achieved tp CR, and 49(62.8%) achieved bp CR. ORRs were 76.9%(95% CI, 66.0%-85.7%) and 93.6%(95% CI,85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine(11.5%) patients experienced asymptomatic left ventricular ejection fraction(LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP(NT-pro BNP), troponin I, or high-sensitivity troponin.Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile,especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.
文摘Background:A positive association between the ABO blood types and survival has been suggested in several malignancies.The aim of this study was to assess the role of the ABO blood types in predicting the prognosis of Chinese patients with curatively resected non-small cell lung cancer(NSCLC).Methods:We retrospectively analyzed 1601 consecutive Chinese patients who underwent curative surgery for NSCLC between January 1,2005 and December 31,2009.The relationship between the ABO blood types and survival was investigated.In addition,univariate and multivariate analyses were performed.Results:Group 1(patients with the blood type O or B) had significantly prolonged overall survival(OS) compared with group 2(patients with the blood type A or AB),with a median OS of 74.9 months versus 61.5 months[hazard ratio(HR) 0.83;95%confidence interval(CI) 0.72-0.96;P = 0.015].Additionally,group 1 had significantly longer disease-free survival(DFS;HR 0.86;95%CI 0.76-0.98;P = 0.022) and locoregional relapse-free survival(LRFS;HR 0.79;95%CI 0.64-0.98;P = 0.024) than group 2.The association was not significantly modified by other risk factors for NSCLC,including smoking status,pathologic tumor-node-metastasis stage,pT category,pN category,and chemotherapy.Conclusions:There is an association between the ABO blood types and the survival of Chinese patients with resected NSCLC.Patients with the blood type O or B had significantly prolonged OS,DFS,and LRFS compared with those with the blood type A or AB.
基金supported by grants from the National Natural Science Foundation of China (No. 30972785,30801376,30973505,30945201)Sun Yat-sen Excellent Medicine Youth Project,the Science and Technology Foundation of Guangdong Province (No.2009B030801005,2008B030301092)Foundation of Guangzhou Science and Technology Bureau (No.2009Y-C011-1)
文摘Ubiquitin-conjugating enzyme 9(Ubc9),the sole conjugating enzyme for sumoylation,regulates protein function and plays an important role in tumorigenesis.Whether Ubc9 is involved in the chemoresistance of breast cancer remains unknown.In this study,we aimed to evaluate the contribution of Ubc9 in the chemoresistance of breast cancer.Immunohistochemistry(IHC) was used to examine the expression level of Ubc9.Chi-square test,Wilcoxon test,and one-way ANOVA were applied to analyze the relationship between Ubc9 expression,clinicopathologic features,and clinical response to neoadjuvant chemotherapy.The significance of variables for survival was analyzed by the Cox proportional hazards model in a multivariate analysis.Kaplan-Meier survival curves were plotted and log-rank test was performed.The proportion of Ubc9-positive cells was higher in invasive ductal carcinoma than in normal breast tissues [(48.48 ± 17.94)% vs.(5.82 ± 2.80)%,P < 0.001].High Ubc9 expression was associated with poor differentiation(χ2 = 6.538,P = 0.038),larger tumor size(χ2 = 4.701,P = 0.030),advanced clinical stage(χ2 = 4.651,P = 0.031),lymph node metastasis(χ2 = 9.913,P = 0.010),basal-like phenotype(χ2 = 8.660,P = 0.034),and poor clinical response to neoadjuvant chemotherapy(χ2 = 11.09,P = 0.001).The expected 6-year cumulative disease-free survival rate was 87.32% in patients with low Ubc9 expression compared to 68.78% in those with high Ubc9 expression(χ2 = 4.289,P = 0.038).These data indicate that high Ubc9 expression correlates with poor response to chemotherapy and poor clinical prognosis.
基金Natural Science Foundation of China.Grant Numbers:82173054,81621004,81720108029,82002782 Basic and Applied Basic Research Foundation of Guangdong Province.Grant Number:2022A1515110069 Strategic Priority Research Program of Chinese Academy of Sciences.Grant Number:XDB29040100 Guangdong Science and Technology Department.Grant Number:2022B1515020048 Clinical Innovation Research Program of Bioland Laboratory.Grant Number:2018GZR0201004 Guangzhou Science Technology and Innovation Commission.Grant Number:202102010148 Bureau of Science and Technology of Guangzhou.Grant Number:20212200003 Program for Guangdong Introducing Innovative and Enterpreneurial Teams.Grant Number:2019BT02Y198。
文摘Background As a rapid-progressing tumor,breast malignant phyllodes tumors(PTs)are challenged by the lack of effective therapeutic strategies and suitable prognostic markers.This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression,and to identify a novel prognosis marker and treatment target of breast malignant PTs.Methods The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing(scRNA-seq),immunostaining,real-time PCR and other methodologies.Functional experiments including proliferation assay,colony formation assay,transwell assay,and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs.The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft(PDX)model.Transcriptome sequencing,proteomic analysis,co-immunoprecipitation,and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism.Results In this study,the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in theα-SMA+fibroblast subset.Furthermore,a progressive elevation in the level of CD146 was observed with the malignant progression of PTs.More importantly,CD146 was found to serve as an independent predictor for recurrence in PT patients.Furthermore,CD146 was found to augment the viability and invasion of PTs.Mechanistically,CD146 acted as a protective“shield”to prevent the degradation of Discoidin,CUB,and LCCL domain-containing protein 2(DCBLD2),thereby activating the phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway and enhancing malignant behaviors of PT cells.In the malignant PT organoid and PDX model,a significant suppression of malignant PT growth was observed after the application of AA98.Conclusions These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs.The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.
基金supported by grants from the Director Foundation of Sun Yat-sen university Cancer Center(PT12020401)the National Key Research and Development Program of China(No.2021YFC2500905)+1 种基金the National Natural Science Foundation of China(No.82073121)Guangdong Basic and Applied Basic Research Foundation(No.2020A1515010041).
文摘Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation,and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors.Moreover,tumor-derived apoptotic extracellular vesicles(apoEVs)are inevitably phagocytosed by live tumor cells,promoting tumor heterogeneity.Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence.Herein,we conducted a series of in vivo and in vitro experiments,and we report that tumor-derived apoEVs promoted lung adenocarcinoma(LUAD)metastasis,self-renewal and chemoresistance.Mechanistically,we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2.In addition,we found that ALDH1A1,which was transported by apoEVs,activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells.Furthermore,targeting apoEVs-ALDH1A1 significantly abrogated these effects.Collectively,our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations,and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.
基金funding from the National Natural Science Foundation of China(Grants No.82203435,82203703,82203141,and 82102865)Guangdong Basic and Applied Basic Research Foundation(Grant No.2021A1515111138)+1 种基金Guangzhou Science and Technology Plan Project Support(Grant No.2023A04J2103)the China Postdoctoral Science Foundation(Grants No.2022M713576 and 2022T150757).
文摘Background:TP53 mutations and homologous recombination deficiency(HRD)occur frequently in breast cancer.However,the characteristics of TP53 pathogenic mutations in breast cancer patients with/without HRD are not clear.Methods:Clinical next-generation sequencing(NGS)of both tumor and paired blood DNA from 119 breast cancer patients(BRCA-119 cohort)was performed with a 520-gene panel.Mutations,tumor mutation burden(TMB),and genomic HRD scores were assessed from NGS data.NGS data from 47 breast cancer patients in the HRD test cohort were analyzed for further verification.Results:All TP53 pathogenic mutations in patients had somatic origin,which was associated with the protein expression of estrogen receptor and progestogen receptor.Compared to patients without TP53 pathologic mutations,patients with TP53 pathologic mutations had higher levels of HRD scores and different genomic alterations.The frequency of TP53 pathologic mutation was higher in the HRDhigh group(HRD score≥42)relative to that in the HRD-low group(HRD score<42).TP53 has different mutational characteristics between the HRD-low and HRD-high groups.TP53-specific mutation subgroups had diverse genomic features and TMB.Notably,TP53 pathogenic mutations predicted the HRD status of breast cancer patients with an area under the curve(AUC)of 0.61.TP53-specific mutations,namely HRD-low mutation,HRD-high mutation,and HRD common mutation,predicted the HRD status of breast cancer patients with AUC values of 0.32,0.72,and 0.58,respectively.Interestingly,TP53 HRD-high mutation and HRD common mutation combinations showed the highest AUC values(0.80)in predicting HRD status.Conclusions:TP53-specific mutation combinations predict the HRD status of patients,indicating that TP53 pathogenic mutations could serve as a potential biomarker for poly-ADP-ribose polymerase(PARP)inhibitors in breast cancer patients.
基金supported by the National Natural Science Foundation of China(82173054,82222029,82203085)the Guangdong Basic and Applied Basic Research Foundation(2022B1515020048,2022B1515020101,China)Guangzhou Science,Technology and Innovation Commission(202102010148,China).
文摘Breast phyllodes tumor(PT)is a rare fibroepithelial neoplasm with potential malignant behavior.Long non-coding RNAs(lncRNAs)play multifaceted roles in various cancers,but their involvement in breast PT remains largely unexplored.In this study,microarray was leveraged for the first time to investigate the role of lncRNA in PT.We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT,and its overexpression endowed PT with high tumor grade and adverse prognosis.Furthermore,we elucidated that ZFPM2-AS1 promotes the proliferation,migration,and invasion of malignant PT in vitro.Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft(PDX)model could effectively inhibit tumor progression in vivo.Mechanistically,our findings showed that ZFPM2-AS1 is competitively bound to CDC42,inhibiting ACK1 and STAT1 activation,thereby launching the transcription of TNFRSF19.In conclusion,our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT,and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.
