期刊
CANCER RESEARCH
卷 81, 期 3, 页码 539-551出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-1171
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资金
- DOD Breast Cancer Research Program Breakthrough Award [BC151357]
- DOD Breast Cancer Research Program Expansion Award [BC181341]
- NIH [R01CA221303]
- Huntsman Cancer Institute
- NIH/NCI [P30 CA042014]
- CDMRP [BC181341, 1102151] Funding Source: Federal RePORTER
The study examined the response of breast cancer patients with tumors expressing estrogen receptor a (ER) to hormone therapies and the reasons for potential relapse. Mutant ER induced differential expression of numerous genes, affecting gene expression and chromatin accessibility in breast cancer progression.
While breast cancer patients with tumors that express estrogen receptor a (ER) generally respond well to hormone therapies that block ER activity, a significant number of patients relapse. Approximately 30% of these recurrences harbor activating mutations in the ligand binding domain (LBD) of ER, which have been shown to confer ligand-independent function. However, much is still unclear regarding the effect of mutant ER beyond its estrogen independence. To investigate the molecular effects of mutant ER, we developed multiple isogenic ER-mutant cell lines for the most common LBD mutations, Y537S and D538G. These mutations induced differential expression of thousands of genes, themajority of which were mutant allele specific and were not observed upon estrogen treatment of wild-type (WT) cells. These mutant-specific genes showed consistent differential expression across ER-mutant lines developed in other laboratories. WT cells with long-term estrogen exposure only exhibited some of these transcriptional changes, suggesting that mutant ER causes novel regulatory effects that are not simply due to constant activity. While ER mutations exhibited minor effects on ER genomic binding, with the exception of ligand independence, ER mutations conferred substantial differences in chromatin accessibility. Mutant ER was bound to approximately a quarter of mutant-enriched accessible regions that were enriched for other DNA binding factors, including FOXA1, CTCF, and OCT1. Overall, our findings indicate that mutant ER causes several consistent effects on gene expression, both indirectly and through constant activity. Significance: This study demonstrates the multiple roles of mutant ER in breast cancer progression, including constant ER activity and secondary regulatory effects on gene expression and chromatin accessibility. [GRAPHICS] .
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