Cdh1 and Pik3ca mutations cooperate to induce Immune-Related Invasive Lobular Carcinoma of the Breast
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA420068 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:CDH1 and PIK3CA are the two most frequently mutated genes in Invasive Lobular Carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which - Immune-Related (IR) - is associated with gene expression linked to lymphocyte and macrophage infiltration. Here we report that homozygous deletion of Cdh1 together with mutational activation of Pik3ca in mammary epithelium of genetically modified mice leads to rapid formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression signatures linked to TRegulatory (Treg) cell signaling and immune checkpoint inhibitor pathway activation. Interestingly, these tumors show enhanced Oct4-, Hif1á-, YAP-, Shh-, Rac- and Notch-dependent transcription/signaling, features in common with human IR-ILC and therefore potential targets for therapy. Gene expression profiling reveals immune infiltration and similarities to a subtype of human Invasive Lobular carcinoma.
2018-10-16 | GSE107432 | GEO
Project description:CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.
| S-EPMC6276789 | biostudies-literature
Project description:Invasive lobular breast carcinoma (ILC), one of the major breast cancer histological subtypes, exhibits unique clinical and molecular features compared to the other well-studied ductal cancer subtype (IDC). The pathognomonic feature of ILC is loss of E-cadherin, mainly due to inactivating mutations within the CDH1 gene, but the extent of contribution of this genetic alteration to ILC-specific molecular characteristics remains largely understudied. To profile these features transcriptionally, we conducted single cell RNA sequencing on a panel of IDC and ILC cell lines, as well as an IDC cell line (T47D) with CRISPR-mediated knock out (KO) of CDH1. Inspection of intra-cell line heterogeneity illustrated genetically and transcriptionally distinct subpopulations in multiple cell lines and highlighted rare populations of cells with long latency and an apoptosis-related signature indicative of dormancy. Investigation of CDH1 KO-induced alterations showed transcriptomic membranous systems remodeling, elevated regulon activation resemblance of T47D CDH1 KO cells to ILCs, and suggests IRF1 as a major regulator of the pro-apoptotic and anti-proliferative feature of ILCs.
2020-11-05 | GSE144320 | GEO
Project description:The aim of our study was to identify gene expression profiles of ductal and lobular carcinomas in relation to normal ductal and lobular cells. We examined ten mastectomy specimens from postmenopausal breast cancer patients. Ductal and lobular tumor and normal cells were microdissected from cryosections. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. GCOS pairwise comparison algorithm and rank products have identified multiple genes that are differentially expressed in comparisons between ductal and lobular tumor and normal cell types. The results suggest that these genes are involved in epithelial-mesenchymal transition, TGFbeta and Wnt signaling. These changes are present in both tumor types but appear to be more prominent in lobular carcinomas. Keywords: cell type comparison
2007-03-16 | GSE5764 | GEO
Project description:Breast cancer is categorized by the molecular and histologic presentation of the tumor; with the major histologic subtypes observed in patients being No Special Type (NST; commonly known as Invasive Ductal Carcinoma, IDC) and Invasive Lobular Carcinoma (ILC). ILC are characterized by growth in a single file discohesive manner with stromal infiltration attributed to their hallmark loss of E-cadherin (CDH1). The Cancer Cell Line Encyclopedia (CCLE) currently only lists three ILC cell lines; emphasizing the need to expand the inventory of models available to researchers. Here we report the successful establishment and characterization of a novel ILC cell line, WCRC-25, from a metastatic pleural effusion from a postmenopausal Caucasian woman with metastatic ILC. WCRC-25 is an ER-negative luminal epithelial ILC cell line with both luminal and Her2-like features. It exhibits anchorage independent growth and haptotactic migration towards Collagen I. Sequencing revealed a CDH1 Q706* truncating mutation in WCRC-25, together with mutations in FOXA1, CTCF, BRCA2 and TP53 which were also seen in a series of metastatic lesions from the patient. Copy number analyses revealed amplification and deletion of genes frequently altered in ILC while optical gene mapping (Bionano) revealed novel structural rearrangements. RNA-seq analysis comparing the primary tumor, metastases and the cell line revealed signatures for cell cycle progression and receptor tyrosine kinase signaling. To assess targetability, we treated WCRC-25 with AZD5363 and Alpelisib confirming WCRC-25 as susceptible to PI3K/Akt signaling inhibition as predicted by our RNA sequencing analysis. In conclusion, we report WCRC-25 as a novel ILC cell line with much promise as a valuable research tool to advance our understanding of ILC and its therapeutic vulnerabilities.
2023-12-20 | GSE221512 | GEO
Project description:The aim of our study was to identify gene expression profiles of ductal and lobular carcinomas in relation to normal ductal and lobular cells. We examined ten mastectomy specimens from postmenopausal breast cancer patients. Ductal and lobular tumor and normal cells were microdissected from cryosections. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. GCOS pairwise comparison algorithm and rank products have identified multiple genes that are differentially expressed in comparisons between ductal and lobular tumor and normal cell types. The results suggest that these genes are involved in epithelial-mesenchymal transition, TGFbeta and Wnt signaling. These changes are present in both tumor types but appear to be more prominent in lobular carcinomas. Ten surgical specimens obtained by mastectomy from postmenopausal patients with invasive ductal (IDC) and lobular breast (ILC) carcinomas were investigated. Of these, 5 were IDCs and 5 were ILCs. Tumor and normal tissues from the same mammary gland were identified by an experienced pathologist, snap-frozen in liquid nitrogen and stored at -80ºC for further analysis. Microdissection, RNA isolation, amplification, labeling and microarray analysis are described in sample definitions. Samples from particular cell types (normal ductal, normal lobular, tumor ductal, tumor lobular - 10, 10, 5, 5 samples, respectively) were considered as biological replicates and were compared in between.
2007-11-01 | E-GEOD-5764 | biostudies-arrayexpress
Project description:Background: The prognostic value of histologic grade (HG) in invasive lobular carcinoma (ILC) remains uncertain, and most ILC tumors are graded as HG2. Genomic grade (GG) is a 97-gene signature that improves the prognostic value of HG. This study evaluates whether GG may overcome the limitations of HG in ILC. Methods: Gene expression data were generated from frozen tumor samples, and GG calculated according to the expression of 97 genes. The prognostic value of GG was assessed in a stratified Cox regression model for invasive disease-free survival (IDFS) and overall survival (OS).
2016-10-15 | GSE88770 | GEO
Project description:As part of the RATHER (RAtional THERapy for breast cancer: individualized treatment for difficult-to-treat breast cancer subtypes) consortium, expression profiling of 144 untreated primary invasive lobular carcinoma (ILC) breast cancer tissues and 15 ILC cell lines was performed using microarray. Gene expression profiling of 144 ILC breast cancers and 15 ILC cell lines
2016-01-05 | E-GEOD-68057 | biostudies-arrayexpress
Project description:Invasive lobular carcinoma (ILC) of the breast accounts for 5-15% of breast cancers and is characterized by loss of E-cadherin and believed to arise via a linear histological progression. Genomic studies have identified a clonal relationship between ILC and concurrent lobular carcinoma in situ (LCIS) lesions, suggesting that LCIS may be a precursor lesion. It has been shown that an LCIS diagnosis confers a 15-20% risk of progression to ILC, over a lifetime. Currently no molecular test or markers can identify LCIS lesions likely to progress to ILC. Since microRNA (miRNA) expression changes have been detected in a number of other cancer types, we explored whether their dysregulation might be detected during progression from LCIS to ILC. Using the Illumina miRNA profiling platform, designed for simultaneous analysis of 470 mature miRNAs, we analyzed the profiles of archived normal breast epithelium, LCIS lesions found alone, LCIS lesions concurrent with ILC, and the concurrent ILCs, as a model of linear histological progression toward ILC. We identified two sets of differentially expressed miRNAs, the first set highly expressed in normal epithelium, including hsa-miR-224, -139, -10b, -450, 140 and -365 and the second set upregulated during lobular neoplasia, including hsa-miR-375, -203, -425-5p, -183, -565 and -182. Using quantitative RT-PCR, we validated a trend of increased expression for hsa-mir-375, hsa-mir-182, and hsa-mir-183 correlating with ILC progression. As we detected increased expression of hsa-miR-375 in LCIS lesions synchronous with ILC, we sought to determine whether hsa-mir-375 might induce phenotypes reminiscent of lobular neoplasia by expressing it in the MCF10A 3D culture model of mammary acinar morphogenesis. Increased expression of hsa-miR-375 resulted in loss of cellular organization and acquisition of a hyperplastic phenotype. These data suggest that dysregulated miRNA expression contributes to lobular neoplastic progression. 6 specimens were analyzed in duplicate. One frozen normal lobular epithelium and the matched FFPE (1 month old) normal lobular epithelium. One lobular carcinoma in situ (LCIS) found alone, one LCIS synchronous with an invasive lobular carcinoma (ILC), the synchronous ILC (from a different archived block), and one ILC found alone without presence of any other breast cancer.
2011-04-11 | E-GEOD-28514 | biostudies-arrayexpress
Project description:The identification of lobular caricnoma in situ (LCIS) in a patient's specimen confers and appreciable increased risk of development of future invasive mammary carcinoma. However the study of LCIS presents a challenge as it is usually only recognized in fixed specimens and no good in vivo or in vitro models currently exist. Recent advances in high throughput genomics have made possible comprehensive copy number analysis of lesions such as this. We have characterized LCIS on microdissected cases of archival patient samples using aCGH. We used 4 cases of LCIS with adjacent ILC. Histological sections from 4 cases of LCIS and 4 cases of ILC microdissected, DNA extracted and subjected to whole genome amplification, and aCGH.
2010-12-31 | E-GEOD-20474 | biostudies-arrayexpress