Posted November 14, 2017

Timothy A. Chan, M.D., Ph.D., Sloan Kettering Institute for Cancer Research

Breast cancer-associated death primarily occurs when breast cancer cells spread, or metastasize, from the primary tumor to other parts of the body. While several cellular pathways have been linked to the progression of metastatic disease, key drivers in this complex process have not been identified. In addition to the subtype, stage, grade, and size of a tumor, the presence or absence of specific receptors on tumor cells can influence treatment options for breast cancer patients. While some treatment options are successful, others may be found to be ineffective or lead to resistance over time, supporting the need to identify new therapeutic approaches for breast cancer patients. Dr. Timothy Chan and his colleagues investigate genetic changes that regulate the metastatic progression of breast cancer in order to identify novel therapeutic targets for this disease and improve upon current diagnostics used for breast cancer.

With support from a Fiscal Year 2012 Era of Hope Scholar Award, Dr. Chan and his team identified TRIM25, a multifunctional transcription factor, as a keystone protein in metastatic breast cancer. Of the 32 cancer types tested from The Cancer Genome Atlas (TCGA), TRIM25 was most frequently amplified in breast cancer, and elevated TRIM25 expression was significantly associated with poor outcome in the 1,038 TCGA breast cancer tumors analyzed. In a recent publication in Cell Reports, they elucidated the molecular mechanisms regulating TRIM25. Dr. Chan and colleagues obtained both primary and metastatic tissue samples from each of 31 breast cancer patients (20 estrogen receptor-positive [ER+] and 11 triple-negative breast cancer [TNBC] patients) and analyzed their gene expression signatures. A two-tailed gene set enrichment analysis (GSEA2) revealed common metastatic progression mechanisms between the ER+ and TNBC datasets, indicating that these mechanisms are independent of hormonal status. In addition, other detailed analyses revealed TRIM25 as a master regulator protein that can influence multiple downstream transcription programs involved in the metastatic progression of breast cancer. Dr. Chan and his team also showed that increasing or decreasing TRIM25 expression in TNBC cell lines resulted in increased or decreased lung metastases in a mouse model of breast cancer, respectively. Furthermore, out of the 189 molecular signature database (MSigDB) oncogenic gene signatures analyzed, the research team reported that the strongest enrichment was for a signature related to differentiation of embryonic stem cells, suggesting that TRIM25 may be involved in the maintenance of stemness for breast cancer tumor cells. This cutting-edge research conducted by Dr. Chan and his team highlights TRIM25 as a novel breast cancer therapeutic target.

Publication:

Walsh LA, Alvarez MJ, Sabio EY, et al. 2017. An integrated systems biology approach identifies TRIM25 as a key determinant of breast cancer metastasis. Cell Reports 20:1623-1640.

Link:

Publication and Technical Abstracts: Targeting Master Regulators of the Breast Cancer Metastasis Transcriptome

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