Susrutha Puthanmadhom Narayanan, Abdalla M Wedn, Osama Shiraz Shah, Jian Chen, Daniel D Brown, Priscilla F McAuliffe, Steffi Oesterreich, Adrian V Lee
{"title":"转录组分析发现浸润性小叶乳腺癌中富含 cAMP/PKA/CREB 信号。","authors":"Susrutha Puthanmadhom Narayanan, Abdalla M Wedn, Osama Shiraz Shah, Jian Chen, Daniel D Brown, Priscilla F McAuliffe, Steffi Oesterreich, Adrian V Lee","doi":"10.1186/s13058-024-01900-y","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies.</p><p><strong>Methods: </strong>Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway.</p><p><strong>Results: </strong>Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition.</p><p><strong>Conclusion: </strong>In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.</p>","PeriodicalId":49227,"journal":{"name":"Breast Cancer Research","volume":null,"pages":null},"PeriodicalIF":7.4000,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526681/pdf/","citationCount":"0","resultStr":"{\"title\":\"Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer.\",\"authors\":\"Susrutha Puthanmadhom Narayanan, Abdalla M Wedn, Osama Shiraz Shah, Jian Chen, Daniel D Brown, Priscilla F McAuliffe, Steffi Oesterreich, Adrian V Lee\",\"doi\":\"10.1186/s13058-024-01900-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies.</p><p><strong>Methods: </strong>Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway.</p><p><strong>Results: </strong>Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition.</p><p><strong>Conclusion: </strong>In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. 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Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.</p>\",\"PeriodicalId\":49227,\"journal\":{\"name\":\"Breast Cancer Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":7.4000,\"publicationDate\":\"2024-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11526681/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Breast Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13058-024-01900-y\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13058-024-01900-y","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
摘要
目的:浸润性小叶乳腺癌(ILC)是最常见的特殊类型乳腺癌:浸润性小叶乳腺癌(ILC)是最常见的特殊类型乳腺癌,具有独特的临床病理和分子特征,有别于更常见的浸润性无特殊类型乳腺癌(NST)。尽管存在这些差异,ILC 和 NST 仍被视为单一实体,并且缺乏针对 ILC 的疗法。为了填补这一空白,我们试图找出ILC中可用于靶向治疗的新型分子改变:对来自三个大型公共乳腺癌数据库--瑞典乳腺癌组分析网络(SCAN-B;luminal A ILC N = 263,luminal A NST N = 1162)、癌症基因组图谱(TCGA;luminal A ILC N = 157,luminal A NST N = 307)和国际乳腺癌分子分类联盟(METABRIC;luminal A ILC N = 65,luminal A NST N = 533)的RNA-seq数据进行了差异基因表达和基因组富集与变异分析。利用 Jaccard 相似性对这些数据集中重叠的差异表达基因所富集的通路进行聚类,以确定在 ILC 中富集的通路。使用cAMP/PKA/CREB信号通路激活剂福斯可林,在ILC、ILC样细胞系、NST细胞系和患者衍生的器官组织(PDOs)中研究了cAMP/PKA/CREB信号通路:结果:SCAN-B中ILC和NST患者的临床病理特征与之前的人群研究相似。在SCAN-B、TCGA和METABRIC中,与NST相比,ILC中cAMP/PKA/CREB相关信号的上调模式一致。用福斯克林处理后,ILC细胞系和器官组织中磷酸化CREB的增加幅度大于NST。根据磷酸化-CREB的测量,NST细胞系中CDH1的CRISPR缺失不会改变细胞对福斯克林的反应。福斯克林处理会抑制 ILC 和 NST 的生长,其中 ILC 细胞系对福斯克林介导的生长抑制更为敏感:结论:在三个独立的数据集中,发现 ILC 的 cAMP/PKA/CREB 信号传导高于 NST。细胞系和类器官模型也验证了这一硅学发现。CDH1 的缺失不足以介导这种表型。未来的研究应探讨cAMP/PKA/CREB信号传导不同的机制以及针对ILC患者进行治疗的潜力。
Transcriptomic analysis identifies enrichment of cAMP/PKA/CREB signaling in invasive lobular breast cancer.
Objective: Invasive lobular breast cancer (ILC) is the most common special type of breast cancer and has unique clinicopathological and molecular hallmarks that differentiate it from the more common invasive carcinoma-no special type (NST). Despite these differences, ILC and NST are treated as a single entity and there is a lack of ILC-targeted therapies. To fill this gap, we sought to identify novel molecular alterations in ILC that could be exploited for targeted therapies.
Methods: Differential gene expression and Geneset Enrichment and Variation analyses were performed on RNA-seq data from three large public breast cancer databases-the Sweden Cancerome Analysis Network-Breast (SCAN-B; luminal A ILC N = 263, luminal A NST N = 1162), The Cancer Genome Atlas (TCGA; luminal A ILC N = 157, luminal A NST N = 307) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; luminal A ILC N = 65, luminal A NST N = 533). Pathways enriched in overlapping differentially expressed genes from these datasets were clustered using Jaccard similarity to identify pathways enriched in ILC. The cAMP/PKA/CREB signaling was studied in ILC, ILC-like and NST cell lines and patient-derived organoids (PDOs) using forskolin, an activator of the pathway.
Results: Clinicopathological features of patients with ILC and NST in SCAN-B were similar to prior population-based studies. There was a consistent pattern of up-regulation of cAMP/PKA/CREB related signaling in ILC compared to NST in SCAN-B, TCGA and METABRIC. Treatment with forskolin resulted in a greater increase in phospho-CREB in ILC cell lines and organoids than NST. CRISPR deletion of CDH1 in NST cell lines did not alter response of cells to forskolin as measured by phospho-CREB. Forskolin treatment caused growth inhibition in ILC and NST, with ILC cell lines being more sensitive to forskolin-mediated growth inhibition.
Conclusion: In three separate datasets, cAMP/PKA/CREB signaling was identified to be higher in ILC than NST. This in silico finding was validated in cell line and organoid models. Loss of CDH1 was not sufficient to mediate this phenotype. Future studies should investigate the mechanisms for differential cAMP/PKA/CREB signaling and the potential for therapeutic targeting in patients with ILC.
期刊介绍:
Breast Cancer Research, an international, peer-reviewed online journal, publishes original research, reviews, editorials, and reports. It features open-access research articles of exceptional interest across all areas of biology and medicine relevant to breast cancer. This includes normal mammary gland biology, with a special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal covers preclinical, translational, and clinical studies with a biological basis, including Phase I and Phase II trials.