Patten, Darren K, Corleone, Giacomo, Gyorffy, Balazs, Perone, Ylenia, Slaven, Neil, Barozzi, Iros, Erdos, Edina, Saiakhova, Alina, Goddard, Kate, Vingiani, Andrea et al (show 10 more authors)
(2018)
Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.
NATURE MEDICINE, 24 (9).
1469-+.
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Enhancer mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.pdf - Author Accepted Manuscript Download (3MB) | Preview |
Abstract
The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumor evolution is poorly understood. Phenotypic drifts can be transmitted via inheritable transcriptional programs. Cell-type specific transcription is maintained through the activation of epigenetically defined regulatory regions including promoters and enhancers. Here we have annotated the epigenome of 47 primary and metastatic estrogen-receptor (ERα)-positive breast cancer clinical specimens and inferred phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Shared regions contain a unique set of regulatory information including the motif for transcription factor YY1. We identify YY1 as a critical determinant of ERα transcriptional activity promoting tumor growth in most luminal patients. YY1 also contributes to the expression of genes mediating resistance to endocrine treatment. Finally, we used H3K27ac levels at active enhancer elements as a surrogate of intra-tumor phenotypic heterogeneity to track the expansion and contraction of phenotypic subpopulations throughout breast cancer progression. By tracking the clonality of SLC9A3R1-positive cells, a bona fide YY1-ERα-regulated gene, we show that endocrine therapies select for phenotypic clones under-represented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Cell Line, Tumor, Clone Cells, Humans, Breast Neoplasms, Phosphoproteins, Estrogen Receptor alpha, Estrogens, Risk Factors, Transcription, Genetic, Epigenesis, Genetic, Protein Binding, Phenotype, Polymorphism, Single Nucleotide, Female, YY1 Transcription Factor, Enhancer Elements, Genetic, Clonal Evolution, MCF-7 Cells, Sodium-Hydrogen Exchangers |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 15 Feb 2021 08:32 |
| Last Modified: | 18 Jan 2023 23:00 |
| DOI: | 10.1038/s41591-018-0091-x |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3115615 |
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