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Cancer Cell. 2018 Sep 10;34(3):466-482.e6. doi: 10.1016/j.ccell.2018.08.001. Epub 2018 Aug 30.

Epigenetic and Transcriptomic Profiling of Mammary Gland Development and Tumor Models Disclose Regulators of Cell State Plasticity.

Author information

1
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: cdravis@salk.edu.
2
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3
Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Departments of Pharmacology and Medicine, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, CA 92037, USA.
4
Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: wahl@salk.edu.

Abstract

Cell state reprogramming during tumor progression complicates accurate diagnosis, compromises therapeutic effectiveness, and fuels metastatic dissemination. We used chromatin accessibility assays and transcriptional profiling during mammary development as an agnostic approach to identify factors that mediate cancer cell state interconversions. We show that fetal and adult basal cells share epigenetic features consistent with multi-lineage differentiation potential. We find that DNA-binding motifs for SOX transcription factors are enriched in chromatin that is accessible in stem/progenitor cells and inaccessible in differentiated cells. In both mouse and human tumors, SOX10 expression correlates with stem/progenitor identity, dedifferentiation, and invasive characteristics. Strikingly, we demonstrate that SOX10 binds to genes that regulate neural crest cell identity, and that SOX10-positive tumor cells exhibit neural crest cell features.

KEYWORDS:

breast cancer; cancer stem cells; cell state plasticity; intra-tumoral heterogeneity; mammary gland development; mammary stem cells; metastasis; neural crest cells; triple-negative breast cancer

PMID:
30174241
PMCID:
PMC6152943
DOI:
10.1016/j.ccell.2018.08.001
[Indexed for MEDLINE]
Free PMC Article

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