Loss of the multifunctional RNA-binding protein RBM47 as a source of selectable metastatic traits in breast cancer
Sakari Vanharanta,
Christina B Marney,
Weiping Shu,
Manuel Valiente,
Yilong Zou,
Aldo Mele,
Robert B Darnell,
Joan Massagué
Affiliations
Sakari Vanharanta
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, United States; MRC Cancer Unit, University of Cambridge, Cambridge, United Kingdom
Christina B Marney
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
Weiping Shu
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, United States
Manuel Valiente
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, United States
Yilong Zou
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, United States
Aldo Mele
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States
Robert B Darnell
Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, United States; Howard Hughes Medical Institute, The Rockefeller University, New York, United States
Joan Massagué
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, United States; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, United States
The mechanisms through which cancer cells lock in altered transcriptional programs in support of metastasis remain largely unknown. Through integrative analysis of clinical breast cancer gene expression datasets, cell line models of breast cancer progression, and mutation data from cancer genome resequencing studies, we identified RNA binding motif protein 47 (RBM47) as a suppressor of breast cancer progression and metastasis. RBM47 inhibited breast cancer re-initiation and growth in experimental models. Transcriptome-wide HITS-CLIP analysis revealed widespread RBM47 binding to mRNAs, most prominently in introns and 3′UTRs. RBM47 altered splicing and abundance of a subset of its target mRNAs. Some of the mRNAs stabilized by RBM47, as exemplified by dickkopf WNT signaling pathway inhibitor 1, inhibit tumor progression downstream of RBM47. Our work identifies RBM47 as an RNA-binding protein that can suppress breast cancer progression and demonstrates how the inactivation of a broadly targeted RNA chaperone enables selection of a pro-metastatic state.
