Pub Date : 2024-09-13DOI: 10.1186/s13058-024-01876-9
Mohamed Omar, J. Chuck Harrell, Rulla Tamimi, Luigi Marchionni, Cihat Erdogan, Harikrishna Nakshatri, Tan A. Ince
Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan–Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences—expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.
尽管有证据表明原发细胞特征在肿瘤分子模式中占主导地位，但将这些全基因组模式转化为可操作的洞察力一直具有挑战性。本研究介绍了乳腺癌原发细胞特征，与以前开发的基因组特征相比，这些特征在所有乳腺癌亚型和各种临床队列中都具有显著的预后价值。我们以前曾报道过，在人类乳腺癌中，雄激素（AR）、雌激素（ER）和维生素 D（VDR）受体的三重激素受体（THR）共表达模式在蛋白质水平上保持不变。在此，我们根据这些模式开发了相应的 mRNA 标识（THR-50 和 THR-70），以根据 THR 表达水平对乳腺肿瘤进行分类。我们使用 Kaplan-Meier 生存分析、Cox 比例危险回归和无监督聚类对 56 个乳腺癌数据集（5040 名患者）中的 THR mRNA 特征进行了评估。在所有评估的数据集中，THR特征都能有效预测总生存期和无进展生存期，不受亚型、分级或治疗状态的影响，这表明THR特征优于现有的预后特征。此外，他们还划分出三种不同的ER阳性乳腺癌亚型，这些亚型在传统的两种亚型的基础上扩大了生存期。此外，将 THR-70 与免疫特征相结合，还发现了一个以 ER 阴性为主的乳腺癌亚组，其预后非常好，与 ER 阳性病例相当；同时也发现了一个 ER 阴性亚组，其预后明显较差，生存期缩短了 15 倍。THR原发细胞特征为乳腺癌生物学引入了一个新的维度，有可能为整合其他预后生物标志物奠定坚实的基础。这些特征为现有乳腺癌亚型的分层和乳腺癌病例的新分类提供了有用的预后指标。此外，THR特征还有望预测针对AR和/或VDR的激素治疗反应。
{"title":"A triple hormone receptor ER, AR, and VDR signature is a robust prognosis predictor in breast cancer","authors":"Mohamed Omar, J. Chuck Harrell, Rulla Tamimi, Luigi Marchionni, Cihat Erdogan, Harikrishna Nakshatri, Tan A. Ince","doi":"10.1186/s13058-024-01876-9","DOIUrl":"https://doi.org/10.1186/s13058-024-01876-9","url":null,"abstract":"Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures. We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan–Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering. The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences—expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival. The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-10DOI: 10.1186/s13058-024-01880-z
Abraham T. Phung, Jaimin R. Shah, Tao Dong, Tony Reid, Christopher Larson, Ana B. Sanchez, Bryan Oronsky, William C. Trogler, Andrew C. Kummel, Omonigho Aisagbonhi, Sarah L. Blair
Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.
乳腺癌是女性的第二大死因，浸润性导管癌（IDC）和浸润性小叶癌（ILC）是两种最常见的浸润性乳腺癌。虽然雌激素受体阳性（ER+）的浸润性导管癌和浸润性小叶癌的治疗方法类似，但浸润性小叶癌的多发性给检测和治疗带来了挑战，使患者的长期临床预后恶化。随着ILC化疗耐药的文献越来越多，我们需要更多的治疗方案。肿瘤溶解性腺病毒疗法可能是一种很有前景的选择，但癌细胞必须表达柯萨奇病毒和腺病毒受体（CAR），腺病毒疗法才能有效。本研究旨在评估与IDC相比，CAR在ILC中的表达程度，以及CAR表达水平与腺病毒转导效率的相关性。本研究还评估了脂质体封装对转导效率的影响。为了确定CAR在浸润性乳腺癌中的表达特征，36份福尔马林固定石蜡包埋（FFPE）的人类乳腺肿瘤样本通过CAR免疫组化（IHC）进行了检测。使用由 CAR、p120-catenin 和 E-cadherin 组成的多重免疫荧光面板对 CAR 与其他交界蛋白的定位进行了比较。用插入 GFP 转基因（Ad-GFP）的 E1 和 E3 缺失的 5 型腺病毒和 DOTAP 脂质体包裹的 Ad-GFP（DfAd-GFP）以不同的感染倍数（MOIs）转导 ILC 和 IDC 原发肿瘤和细胞系。使用荧光平板阅读器测量转导效率。我们还通过 IHC 评估了 CAR 在人类原发性乳腺癌和细胞系中的表达。我们观察到 IDC 中膜上 CAR、p120-catenin 和 E-cadherin 的表达。在 ILC 中，我们观察到 CAR 和 p120-catenin 在细胞质中表达，而 E-cadherin 则缺失。腺病毒能有效地转导高CAR的IDC细胞系，MOI可低至12.5。在高CAR IDC细胞系中，Ad-GFP的转导与DfAd-GFP相似。相反，Ad-GFP 转导 ILC 细胞系的情况只有在 MOI 为 50 和 100 时才能观察到。此外，Ad-GFP 也不能转导 CAR 阴性的 IDC 细胞系，即使 MOI 超过 100。脂质体封装（DfAd-GFP）在 ILC 细胞系中的转导效率提高了 4 倍，在 CAR 阴性的 IDC 细胞系中提高了 17 倍。本研究表明，由于CAR空间表达的差异，溶瘤腺病毒疗法在ILC中的效果不如IDC。脂质体增强递送可能有利于ILC患者和CAR低表达或阴性的肿瘤患者，从而提高腺病毒的治疗效果。
{"title":"CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency","authors":"Abraham T. Phung, Jaimin R. Shah, Tao Dong, Tony Reid, Christopher Larson, Ana B. Sanchez, Bryan Oronsky, William C. Trogler, Andrew C. Kummel, Omonigho Aisagbonhi, Sarah L. Blair","doi":"10.1186/s13058-024-01880-z","DOIUrl":"https://doi.org/10.1186/s13058-024-01880-z","url":null,"abstract":"Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although tumor cells undergoing epithelial–mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. Our primary culture revealed carcinoma cells expressing diverse epithelial–mesenchymal traits, consistent with epithelial–mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal–epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma.
{"title":"Characteristics and transcriptional regulators of spontaneous epithelial–mesenchymal transition in genetically unperturbed patient-derived non-spindled breast carcinoma","authors":"Huang-Chun Lien, Hui-Chieh Yu, Wen-Hsuan Yu, Su-Fang Lin, Tom Wei-Wu Chen, I-Chun Chen, Li-Ping Hsiao, Ling-Chun Yeh, Yu-Chia Li, Chiao Lo, Yen-Shen Lu","doi":"10.1186/s13058-024-01888-5","DOIUrl":"https://doi.org/10.1186/s13058-024-01888-5","url":null,"abstract":"Although tumor cells undergoing epithelial–mesenchymal transition (EMT) typically exhibit spindle morphology in experimental models, such histomorphological evidence of EMT has predominantly been observed in rare primary spindle carcinomas. The characteristics and transcriptional regulators of spontaneous EMT in genetically unperturbed non-spindled carcinomas remain underexplored. We used primary culture combined with RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and in situ RNA-seq to explore the characteristics and transcription factors (TFs) associated with potential spontaneous EMT in non-spindled breast carcinoma. Our primary culture revealed carcinoma cells expressing diverse epithelial–mesenchymal traits, consistent with epithelial–mesenchymal plasticity. Importantly, carcinoma cells undergoing spontaneous EMT did not necessarily exhibit spindle morphology, even when undergoing complete EMT. EMT was a favored process, whereas mesenchymal–epithelial transition appeared to be crucial for secondary tumor growth. Through scRNA-seq, we identified TFs that were sequentially and significantly upregulated as carcinoma cells progressed through the EMT process, which correlated with increasing VIM expression. Once upregulated, the TFs remained active throughout the EMT process. ZEB1 was a key initiator and sustainer of EMT, as indicated by its earliest significant upregulation in the EMT process, its exact correlation with VIM expression, and the reversal of EMT and downregulation of EMT-upregulated TFs upon ZEB1 knockdown. The correlation between ZEB1 and vimentin expression in triple-negative breast cancer and metaplastic breast carcinoma tumor cohorts further highlighted its role. The immediate upregulation of ZEB2 following that of ZEB1, along with the observation that the knockdown of ZEB1 or ZEB2 downregulates both ZEB1 and ZEB2 concomitant with the reversal of EMT, suggests their functional cooperation in EMT. This finding, together with that of a lack of correlation of SNAI1, SNAI2, and TWIST1 expression with the mesenchymal phenotype, indicated EMT-TFs have a context-dependent role in EMT. Upregulation of EMT-related gene signatures during EMT correlated with poor patient outcomes, highlighting the biological importance of the model. Elevated EMT gene signatures and increased ZEB1 and ZEB2 expression in vimentin-positive compared to vimentin-negative carcinoma cells within the corresponding primary tumor tissue confirmed ZEB1 and ZEB2 as intrinsic, instead of microenvironmentally-induced, EMT regulators, and vimentin as an in vivo indicator of EMT. Our findings provide insights into the characteristics and transcriptional regulators of spontaneous EMT in primary non-spindled carcinoma.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM.
多达三分之一的乳腺癌（BC）患者患有糖尿病（DM）。同时患有乳腺癌和糖尿病（BC-DM）的患者预后会恶化。尽管如此，人们对导致 BC-DM 预后的分子机制仍然知之甚少。通过tRF测序和qRT-PCR检测了肿瘤组织和细胞中的tRF水平。在体外等血糖和高血糖条件下评估了tRF对BC细胞恶性程度的影响。代谢变化通过乳酸、丙酮酸和细胞外酸化率（ECAR）测定进行评估。糖尿病动物模型用于评估 tRF 对 BC 肿瘤生长的影响。研究人员通过RNA测序（RNA-seq）、qRT-PCR、Western印迹、多聚酶谱分析、荧光素酶报告实验和拯救实验来探索tRF在BC-DM中的调控机制。我们发现，tRF-Cys-GCA-029在BC-DM组织和高血糖条件下的BC细胞中被下调。从功能上讲，tRF-Cys-GCA-029的下调以葡萄糖水平依赖性的方式促进了BC细胞的增殖和迁移。值得注意的是，注射 tRF-Cys-GCA-029 mimic 能显著抑制糖尿病小鼠 BC 肿瘤的生长。从机理上讲，tRF-Cys-GCA-029通过两种方式与PRKCG相互作用，调节BC细胞的恶性程度和糖酵解：与PRKCG mRNA的编码序列（CDS）结合，调节其转录；改变多聚体PRKCG mRNA的表达，改变其翻译。tRF-Cys-GCA-029-PRKCG-糖酵解轴可能是 BC-DM 的潜在治疗靶点。
{"title":"Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation","authors":"Yongyi Huang, Cheng Chen, Yang Liu, Binbin Tan, Qin Xiang, Qianqian Chen, Yiling Wang, Wenhan Yang, Jingsong He, Duanyang Zhou, Yuting Wang, Kaiping Gao, Duo Zheng, Rihong Zhai","doi":"10.1186/s13058-024-01870-1","DOIUrl":"https://doi.org/10.1186/s13058-024-01870-1","url":null,"abstract":"Diabetes mellitus (DM) affects up to one-third of breast cancer (BC) patients. Patients with co-existing BC and DM (BC-DM) have worsened BC prognosis. Nevertheless, the molecular mechanisms orchestrating BC-DM prognosis remain poorly understood. tRNA-derived fragments (tRFs) have been shown to regulate cancer progression. However, the biological role of tRFs in BC-DM has not been explored. tRF levels in tumor tissues and cells were detected by tRF sequencing and qRT-PCR. The effects of tRF on BC cell malignancy were assessed under euglycemic and hyperglycemic conditions in vitro. Metabolic changes were assessed by lactate, pyruvate, and extracellular acidification rate (ECAR) assays. Diabetic animal model was used to evaluate the impacts of tRF on BC tumor growth. RNA-sequencing (RNA-seq), qRT-PCR, Western blot, polysome profiling, luciferase reporter assay, and rescue experiments were performed to explore the regulatory mechanisms of tRF in BC-DM. We identified that tRF-Cys-GCA-029 was downregulated in BC-DM tissues and under hyperglycemia conditions in BC cells. Functionally, downregulation of tRF-Cys-GCA-029 promoted BC cell proliferation and migration in a glucose level-dependent manner. tRF-Cys-GCA-029 knockdown also enhanced glycolysis metabolism in BC cells, indicated by increasing lactate/pyruvate production and ECAR levels. Notably, injection of tRF-Cys-GCA-029 mimic significantly suppressed BC tumor growth in diabetic-mice. Mechanistically, tRF-Cys-GCA-029 regulated BC cell malignancy and glycolysis via interacting with PRKCG in two ways: binding to the coding sequence (CDS) of PRKCG mRNA to regulate its transcription and altering polysomal PRKCG mRNA expression to modify its translation. Hyperglycemia-downregulated tRF-Cys-GCA-029 enhances the malignancy and glycolysis of BC cells. tRF-Cys-GCA-029-PRKCG-glycolysis axis may be a potential therapeutic target against BC-DM. ","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141741183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1186/s13058-024-01845-2
Xiaoxia Jin, Shuyun Yang, Xiaoyun Lu, Xudong Chen, Wencheng Dai
Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.
{"title":"Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells","authors":"Xiaoxia Jin, Shuyun Yang, Xiaoyun Lu, Xudong Chen, Wencheng Dai","doi":"10.1186/s13058-024-01845-2","DOIUrl":"https://doi.org/10.1186/s13058-024-01845-2","url":null,"abstract":"Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer. Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells. Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident. ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141259893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1186/s13058-024-01850-5
Mylène Duivon, Justine Lequesne, Antonio Di Meglio, Caroline Pradon, Ines Vaz-Luis, Anne-Laure Martin, Sibille Everhard, Sophie Broutin, Olivier Rigal, Chayma Bousrih, Christelle Lévy, Florence Lerebours, Marie Lange, Florence Joly
Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06–7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05–5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43–36.6, p = 0.010). In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.
{"title":"Inflammation at diagnosis and cognitive impairment two years later in breast cancer patients from the Canto-Cog study","authors":"Mylène Duivon, Justine Lequesne, Antonio Di Meglio, Caroline Pradon, Ines Vaz-Luis, Anne-Laure Martin, Sibille Everhard, Sophie Broutin, Olivier Rigal, Chayma Bousrih, Christelle Lévy, Florence Lerebours, Marie Lange, Florence Joly","doi":"10.1186/s13058-024-01850-5","DOIUrl":"https://doi.org/10.1186/s13058-024-01850-5","url":null,"abstract":"Inflammation could be related to cancer-related cognitive impairment (CRCI) and might be used as a predictive marker of long-term CRCI. We evaluated associations between inflammatory markers assessed at diagnosis of breast cancer and CRCI two years afterwards. Newly diagnosed stage I-III patients with breast cancer from the French CANTO-Cog (Cognitive sub-study of CANTO, NCT01993498) were included at diagnosis (baseline). Serum inflammatory markers (IL-2, IL-4, IL-6, IL-8, IL-10, TNFα, CRP) were assessed at baseline. Outcomes at year 2 post-baseline included overall cognitive impairment (≥ 2 impaired domains) and the following domains: episodic memory, working memory, attention, processing speed, and executive functions. Multivariable logistic regression models evaluated associations between markers and outcomes, controlling for age, education, and baseline cognitive impairment. Among 200 patients, the mean age was 54 ± 11 years, with 127 (64%) receiving chemotherapy. Fifty-three (27%) patients had overall cognitive impairment at both timepoints. Overall cognitive impairment at year 2 was associated with high (> 3 mg/L) baseline CRP (OR = 2.84, 95%CI: 1.06–7.64, p = 0.037). In addition, associations were found between high CRP and processing speed impairment (OR = 2.47, 95%CI:1.05–5.87, p = 0.039), and between high IL-6 and episodic memory impairment (OR = 5.50, 95%CI:1.43–36.6, p = 0.010). In this cohort, high levels of CRP and IL-6 assessed at diagnosis were associated with overall CRCI, processing speed and episodic memory impairments two years later. These findings suggest a potential inflammatory basis for long-term CRCI. CRP may represent an easily measurable marker in clinical settings and be potentially used to screen patients at greater risk of persistent CRCI.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141258799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1186/s13058-024-01824-7
Marie Tollot-Wegner, Marco Jessen, KyungMok Kim, Adrián Sanz-Moreno, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Björn von Eyss
The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. Using transcriptomic approaches, flow cytometry and functional assays, we show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities. TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It may also provide new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers.
{"title":"TRPS1 maintains luminal progenitors in the mammary gland by repressing SRF/MRTF activity","authors":"Marie Tollot-Wegner, Marco Jessen, KyungMok Kim, Adrián Sanz-Moreno, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabe de Angelis, Björn von Eyss","doi":"10.1186/s13058-024-01824-7","DOIUrl":"https://doi.org/10.1186/s13058-024-01824-7","url":null,"abstract":"The transcription factor TRPS1 is a context-dependent oncogene in breast cancer. In the mammary gland, TRPS1 activity is restricted to the luminal population and is critical during puberty and pregnancy. Its function in the resting state remains however unclear. To evaluate whether it could be a target for cancer therapy, we investigated TRPS1 function in the healthy adult mammary gland using a conditional ubiquitous depletion mouse model where long-term depletion does not affect fitness. Using transcriptomic approaches, flow cytometry and functional assays, we show that TRPS1 activity is essential to maintain a functional luminal progenitor compartment. This requires the repression of both YAP/TAZ and SRF/MRTF activities. TRPS1 represses SRF/MRTF activity indirectly by modulating RhoA activity. Our work uncovers a hitherto undisclosed function of TRPS1 in luminal progenitors intrinsically linked to mechanotransduction in the mammary gland. It may also provide new insights into the oncogenic functions of TRPS1 as luminal progenitors are likely the cells of origin of many breast cancers.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140840565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-29DOI: 10.1186/s13058-024-01820-x
Rebecca E. Smith, Brian L. Sprague, Louise M. Henderson, Karla Kerlikowske, Diana L. Miglioretti, Karen J. Wernli, Tracy Onega, Roberta M. diFlorio-Alexander, Anna N.A. Tosteson
Following a breast cancer diagnosis, it is uncertain whether women’s breast density knowledge influences their willingness to undergo pre-operative imaging to detect additional cancer in their breasts. We evaluated women’s breast density knowledge and their willingness to delay treatment for pre-operative testing. We surveyed women identified in the Breast Cancer Surveillance Consortium aged ≥ 18 years, with first breast cancer diagnosed within the prior 6–18 months, who had at least one breast density measurement within the 5 years prior to their diagnosis. We assessed women’s breast density knowledge and correlates of willingness to delay treatment for 6 or more weeks for pre-operative imaging via logistic regression. Survey participation was 28.3% (969/3,430). Seventy-two percent (469/647) of women with dense and 11% (34/322) with non-dense breasts correctly knew their density (p < 0.001); 69% (665/969) of all women knew dense breasts make it harder to detect cancers on a mammogram; and 29% (285/969) were willing to delay treatment ≥ 6 weeks to undergo pre-operative imaging. Willingness to delay treatment did not differ by self-reported density (OR:0.99 for non-dense vs. dense; 95%CI: 0.50–1.96). Treatment with chemotherapy was associated with less willingness to delay treatment (OR:0.67; 95%CI: 0.46–0.96). Having previously delayed breast cancer treatment more than 3 months was associated with an increased willingness to delay treatment for pre-operative imaging (OR:2.18; 95%CI: 1.26–3.77). Understanding of personal breast density was not associated with willingness to delay treatment 6 or more weeks for pre-operative imaging, but aspects of a woman’s treatment experience were. NCT02980848 registered December 2, 2016.
{"title":"Breast density knowledge and willingness to delay treatment for pre-operative breast cancer imaging among women with a personal history of breast cancer","authors":"Rebecca E. Smith, Brian L. Sprague, Louise M. Henderson, Karla Kerlikowske, Diana L. Miglioretti, Karen J. Wernli, Tracy Onega, Roberta M. diFlorio-Alexander, Anna N.A. Tosteson","doi":"10.1186/s13058-024-01820-x","DOIUrl":"https://doi.org/10.1186/s13058-024-01820-x","url":null,"abstract":"Following a breast cancer diagnosis, it is uncertain whether women’s breast density knowledge influences their willingness to undergo pre-operative imaging to detect additional cancer in their breasts. We evaluated women’s breast density knowledge and their willingness to delay treatment for pre-operative testing. We surveyed women identified in the Breast Cancer Surveillance Consortium aged ≥ 18 years, with first breast cancer diagnosed within the prior 6–18 months, who had at least one breast density measurement within the 5 years prior to their diagnosis. We assessed women’s breast density knowledge and correlates of willingness to delay treatment for 6 or more weeks for pre-operative imaging via logistic regression. Survey participation was 28.3% (969/3,430). Seventy-two percent (469/647) of women with dense and 11% (34/322) with non-dense breasts correctly knew their density (p < 0.001); 69% (665/969) of all women knew dense breasts make it harder to detect cancers on a mammogram; and 29% (285/969) were willing to delay treatment ≥ 6 weeks to undergo pre-operative imaging. Willingness to delay treatment did not differ by self-reported density (OR:0.99 for non-dense vs. dense; 95%CI: 0.50–1.96). Treatment with chemotherapy was associated with less willingness to delay treatment (OR:0.67; 95%CI: 0.46–0.96). Having previously delayed breast cancer treatment more than 3 months was associated with an increased willingness to delay treatment for pre-operative imaging (OR:2.18; 95%CI: 1.26–3.77). Understanding of personal breast density was not associated with willingness to delay treatment 6 or more weeks for pre-operative imaging, but aspects of a woman’s treatment experience were. NCT02980848 registered December 2, 2016.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140811508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.1186/s13058-024-01826-5
Jia-Wern Pan, Mohana Ragu, Wei-Qin Chan, Siti Norhidayu Hasan, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Cheng-Har Yip, Pathmanathan Rajadurai, Lai-Meng Looi, Nur Aishah Mohd Taib, Oscar M. Rueda, Carlos Caldas, Suet-Feung Chin, Joanna Lim, Soo-Hwang Teo
Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2− breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2− breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2− samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.
{"title":"Clustering of HR + /HER2− breast cancer in an Asian cohort is driven by immune phenotypes","authors":"Jia-Wern Pan, Mohana Ragu, Wei-Qin Chan, Siti Norhidayu Hasan, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Cheng-Har Yip, Pathmanathan Rajadurai, Lai-Meng Looi, Nur Aishah Mohd Taib, Oscar M. Rueda, Carlos Caldas, Suet-Feung Chin, Joanna Lim, Soo-Hwang Teo","doi":"10.1186/s13058-024-01826-5","DOIUrl":"https://doi.org/10.1186/s13058-024-01826-5","url":null,"abstract":"Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2− breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2− breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2− samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140635811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-22DOI: 10.1186/s13058-024-01821-w
Mi-ri Kwon, Yoosoo Chang, Soo-Youn Ham, Yoosun Cho, Eun Young Kim, Jeonggyu Kang, Eun Kyung Park, Ki Hwan Kim, Minjeong Kim, Tae Soo Kim, Hyeonsoo Lee, Ria Kwon, Ga-Young Lim, Hye Rin Choi, JunHyeok Choi, Shin Ho Kook, Seungho Ryu
Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women. We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI’s performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A–D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories. Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7–77.3] vs. 67.1% [95% CI, 58.8–74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9–93.2] vs. 77.6% [95% CI, 61.7–77.9]), PPV (1.5% [95% CI, 1.2–1.9] vs. 0.5% [95% CI, 0.4–0.6]), recall rate (7.1% [95% CI, 6.9–7.2] vs. 22.5% [95% CI, 22.2–22.7]), and AUC values (0.8 [95% CI, 0.76–0.84] vs. 0.74 [95% CI, 0.7–0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category. AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.
人工智能（AI）算法对乳腺X光筛查的独立评估尚未在亚洲妇女的大型筛查队列中得到很好的证实。我们比较了放射科医生和人工智能独立检测在韩国女性中考虑乳腺密度的筛查数字乳腺X光摄影的性能。我们回顾性地纳入了 2009 年至 2020 年期间接受初次数字乳腺 X 光摄影筛查的 89,855 名韩国女性。根据国家癌症登记处的数据，筛查乳房 X 射线照相术后 12 个月内的乳腺癌是参考标准。Lunit 软件用于确定恶性肿瘤概率分数，乳腺癌检测的临界值为 10%。根据乳腺放射科医生的记录，将人工智能的性能与乳腺成像报告和数据系统的最终分类进行了比较。根据放射科医生和人工智能的评估结果，乳腺密度被分为四类（A-D）。对不同乳腺密度类别的性能指标（癌症检出率[CDR]、灵敏度、特异性、阳性预测值[PPV]、召回率和接收者工作特征曲线下面积[AUC]）进行了比较。参与者的平均年龄为 43.5 ± 8.7 岁，在 12 个月内发现了 143 例乳腺癌病例。CDR（1.1/1000 次检查）和灵敏度值显示，放射科医生和人工智能结果之间没有明显差异（69.9% [95% 置信区间 [CI], 61.7-77.3] vs. 67.1% [95% CI, 58.8-74.8]）。不过，人工智能算法的特异性（93.0% [95% CI, 92.9-93.2] vs. 77.6% [95% CI, 61.7-77.9]）、PPV（1.5% [95% CI, 1.2-1.9] vs. 0.5% [95% CI, 0.4-0.6]）、召回率（7.1% [95% CI, 6.9-7.2] vs. 22.5% [95% CI, 22.2-22.7]）和 AUC 值（0.8 [95% CI, 0.76-0.84] vs. 0.74 [95% CI, 0.7-0.78] ）（所有 P <0.05）。放射科医生和基于人工智能的结果在非致密类别中表现最佳；在异质致密类别中，放射科医生的 CDR 和灵敏度更高（P = 0.059）。不过，在包括极度致密类别在内的所有类别中，基于人工智能的结果在特异性、PPV 和召回率方面始终更胜一筹。基于人工智能的软件灵敏度略低，但差异无统计学意义。不过，它在召回率、特异性、PPV 和 AUC 方面都优于放射科医生，在极致密乳腺组织方面差距最为明显。
{"title":"Screening mammography performance according to breast density: a comparison between radiologists versus standalone intelligence detection","authors":"Mi-ri Kwon, Yoosoo Chang, Soo-Youn Ham, Yoosun Cho, Eun Young Kim, Jeonggyu Kang, Eun Kyung Park, Ki Hwan Kim, Minjeong Kim, Tae Soo Kim, Hyeonsoo Lee, Ria Kwon, Ga-Young Lim, Hye Rin Choi, JunHyeok Choi, Shin Ho Kook, Seungho Ryu","doi":"10.1186/s13058-024-01821-w","DOIUrl":"https://doi.org/10.1186/s13058-024-01821-w","url":null,"abstract":"Artificial intelligence (AI) algorithms for the independent assessment of screening mammograms have not been well established in a large screening cohort of Asian women. We compared the performance of screening digital mammography considering breast density, between radiologists and AI standalone detection among Korean women. We retrospectively included 89,855 Korean women who underwent their initial screening digital mammography from 2009 to 2020. Breast cancer within 12 months of the screening mammography was the reference standard, according to the National Cancer Registry. Lunit software was used to determine the probability of malignancy scores, with a cutoff of 10% for breast cancer detection. The AI’s performance was compared with that of the final Breast Imaging Reporting and Data System category, as recorded by breast radiologists. Breast density was classified into four categories (A–D) based on the radiologist and AI-based assessments. The performance metrics (cancer detection rate [CDR], sensitivity, specificity, positive predictive value [PPV], recall rate, and area under the receiver operating characteristic curve [AUC]) were compared across breast density categories. Mean participant age was 43.5 ± 8.7 years; 143 breast cancer cases were identified within 12 months. The CDRs (1.1/1000 examination) and sensitivity values showed no significant differences between radiologist and AI-based results (69.9% [95% confidence interval [CI], 61.7–77.3] vs. 67.1% [95% CI, 58.8–74.8]). However, the AI algorithm showed better specificity (93.0% [95% CI, 92.9–93.2] vs. 77.6% [95% CI, 61.7–77.9]), PPV (1.5% [95% CI, 1.2–1.9] vs. 0.5% [95% CI, 0.4–0.6]), recall rate (7.1% [95% CI, 6.9–7.2] vs. 22.5% [95% CI, 22.2–22.7]), and AUC values (0.8 [95% CI, 0.76–0.84] vs. 0.74 [95% CI, 0.7–0.78]) (all P < 0.05). Radiologist and AI-based results showed the best performance in the non-dense category; the CDR and sensitivity were higher for radiologists in the heterogeneously dense category (P = 0.059). However, the specificity, PPV, and recall rate consistently favored AI-based results across all categories, including the extremely dense category. AI-based software showed slightly lower sensitivity, although the difference was not statistically significant. However, it outperformed radiologists in recall rate, specificity, PPV, and AUC, with disparities most prominent in extremely dense breast tissue.","PeriodicalId":9222,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140635151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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