ArticleBreast cancer research : BCR2015
A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation.
Article in Breast cancer research : BCR, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 28 citations in OpenAlex.
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- Accurate determination of CRISPR-mediated gene fitness in transplantable tumours.Nature communications · 2022Article
- Combined RNA/tissue profiling identifies novel Cancer/testis genes.Molecular oncology · 2021Article
- EFNA4 promotes cell proliferation and tumor metastasis in hepatocellular carcinoma through a PIK3R2/GSK3β/β-catenin positive feedback loop.Molecular therapy. Nucleic acids · 2021Article
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- Ephrin A4-ephrin receptor A10 signaling promotes cell migration and spheroid formation by upregulating NANOG expression in oral squamous cell carcinoma cells.Scientific reports · 2021Article
- Expression Pattern and Prognostic Value of EPHA/EFNA in Breast Cancer by Bioinformatics Analysis: Revealing Its Importance in Chemotherapy.BioMed research international · 2021Article
- Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing.Cell · 2019Article
- Engineered in-vitro cell line mixtures and robust evaluation of computational methods for clonal decomposition and longitudinal dynamics in cancer.Scientific reports · 2017Article
- CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion.Nucleic acids research · 2017Article
- CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.Nature communications · 2017Article
- Scalable whole-genome single-cell library preparation without preamplification.Nature methods · 2017Article
- EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth.Journal of hematology & oncology · 2017Article
- Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer.Journal of proteome research · 2016Article
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14 authors at 5 institutions in 3 countries.
Funding
Abstract
introductionThe extracellular signals regulating mammary epithelial cell growth are of relevance to understanding the pathophysiology of mammary epithelia, yet they remain poorly characterized. In this study, we applied an unbiased approach to understanding the functional role of signalling molecules in several models of normal physiological growth and translated these results to the biological understanding of breast cancer subtypes.
methodsWe developed and utilized a cytogenetically normal clonal line of hTERT immortalized human mammary epithelial cells in a fibroblast-enhanced co-culture assay to conduct a genome-wide small interfering RNA (siRNA) screen for evaluation of the functional effect of silencing each gene. Our selected endpoint was inhibition of growth. In rigorous postscreen validation processes, including quantitative RT-PCR, to ensure on-target silencing, deconvolution of pooled siRNAs and independent confirmation of effects with lentiviral short-hairpin RNA constructs, we identified a subset of genes required for mammary epithelial cell growth. Using three-dimensional Matrigel growth and differentiation assays and primary human mammary epithelial cell colony assays, we confirmed that these growth effects were not limited to the 184-hTERT cell line. We utilized the METABRIC dataset of 1,998 breast cancer patients to evaluate both the differential expression of these genes across breast cancer subtypes and their prognostic significance.
resultsWe identified 47 genes that are critically important for fibroblast-enhanced mammary epithelial cell growth. This group was enriched for several axonal guidance molecules and G protein-coupled receptors, as well as for the endothelin receptor PROCR. The majority of genes (43 of 47) identified in two dimensions were also required for three-dimensional growth, with HSD17B2, SNN and PROCR showing greater than tenfold reductions in acinar formation. Several genes, including PROCR and the neuronal pathfinding molecules EFNA4 and NTN1, were also required for proper differentiation and polarization in three-dimensional cultures. The 47 genes identified showed a significant nonrandom enrichment for differential expression among 10 molecular subtypes of breast cancer sampled from 1,998 patients. CD79A, SERPINH1, KCNJ5 and TMEM14C exhibited breast cancer subtype-independent overall survival differences.
conclusionDiverse transmembrane signals are required for mammary epithelial cell growth in two-dimensional and three-dimensional conditions. Strikingly, we define novel roles for axonal pathfinding receptors and ligands and the endothelin receptor in both growth and differentiation.
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