期刊
CELL REPORTS
卷 20, 期 7, 页码 1623-1640出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.07.052
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资金
- Canadian Institutes of Health Research PDF Award [MFE-127325]
- Department for Defense Era of Hope Grant [BC120568]
- STARR Cancer Consortium
- Geoffrey Beene Cancer Center
- MSKCC Metastasis Research Center
- NIDDK [1 DP2 DK098093-01]
- CADC pilot grant
- NCI Cancer Support Grant [P30 CA008748]
- CDMRP [542283, BC120568] Funding Source: Federal RePORTER
At the root of most fatal malignancies are aberrantly activated transcriptional networks that drive metastatic dissemination. Although individual metastasis-associated genes have been described, the complex regulatory networks presiding over the initiation and maintenance of metastatic tumors are still poorly understood. There is untapped value in identifying therapeutic targets that broadly govern coordinated transcriptional modules dictating metastatic progression. Here, we reverse engineered and interrogated a breast cancer-specific transcriptional interaction network (interactome) to define transcriptional control structures causally responsible for regulating genetic programs underlying breast cancer metastasis in individual patients. Our analyses confirmed established pro-metastatic transcription factors, and they uncovered TRIM25 as a key regulator of metastasis-related transcriptional programs. Further, in vivo analyses established TRIM25 as a potent regulator of metastatic disease and poor survival outcome. Our findings suggest that identifying and targeting keystone proteins, like TRIM25, can effectively collapse transcriptional hierarchies necessary for metastasis formation, thus representing an innovative cancer intervention strategy.
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