Mammary molecular portraits reveal lineage-specific features and progenitor cell vulnerabilities
| Autor: | Dalia Barsyte-Lovejoy, Julie Livingstone, Ruth Isserlin, Geneviève Deblois, Hui Fang, Daniel D. De Carvalho, Tiago Medina, Thomas Kislinger, Paul C. Boutros, Pirashaanthy Tharmapalan, Alison E. Casey, Stefan Hofer, Swneke D. Bailey, Erik Drysdale, Hal K. Berman, Gary D. Bader, Mona Shehata, Rama Khokha, Mathieu Lupien, Yu-Jia Shiah, Rajat Singhania, Cheryl H. Arrowsmith, Stefan Knapp, Paul Waterhouse, Ankit Sinha, Hyeyeon Kim, Jennifer Cruickshank |
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| Rok vydání: | 2018 |
| Předmět: |
Epigenomics
0301 basic medicine Proteome Cell Proteomics Medical and Health Sciences Transgenic Epigenesis Genetic Mice Risk Factors RNA Neoplasm Research Articles Progesterone Tumor DNA Neoplasm Biological Sciences Up-Regulation 3. Good health Cell biology medicine.anatomical_structure DNA methylation Neoplastic Stem Cells Stem cell Mice Transgenic Breast Neoplasms Biology Cell Line Tools 03 medical and health sciences Genetic Cell Line Tumor medicine Animals Humans Cell Lineage Epigenetics Progenitor cell Progenitor DNA Cell Biology DNA Methylation 030104 developmental biology Neoplasm RNA Tumor Suppressor Protein p53 Transcriptome Epigenesis Developmental Biology |
| Zdroj: | The Journal of cell biology, vol 217, iss 8 The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Casey et al. integrate epigenomic, transcriptomic, and proteomic profiling of primary basal and luminal mammary cells to identify master epigenetic regulators of the mammary epithelium and uncover stem and progenitor cell vulnerabilities. They develop a pipeline to identify drugs that abrogate progenitor cell activity in normal and high-risk breast cancer patient samples in vitro and in vivo. The mammary epithelium depends on specific lineages and their stem and progenitor function to accommodate hormone-triggered physiological demands in the adult female. Perturbations of these lineages underpin breast cancer risk, yet our understanding of normal mammary cell composition is incomplete. Here, we build a multimodal resource for the adult gland through comprehensive profiling of primary cell epigenomes, transcriptomes, and proteomes. We define systems-level relationships between chromatin–DNA–RNA–protein states, identify lineage-specific DNA methylation of transcription factor binding sites, and pinpoint proteins underlying progesterone responsiveness. Comparative proteomics of estrogen and progesterone receptor–positive and –negative cell populations, extensive target validation, and drug testing lead to discovery of stem and progenitor cell vulnerabilities. Top epigenetic drugs exert cytostatic effects; prevent adult mammary cell expansion, clonogenicity, and mammopoiesis; and deplete stem cell frequency. Select drugs also abrogate human breast progenitor cell activity in normal and high-risk patient samples. This integrative computational and functional study provides fundamental insight into mammary lineage and stem cell biology. |
| Databáze: | OpenAIRE |
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