Document Type

Article

Publication Date

11-26-2019

Keywords

JGM

JAX Source

Cell Rep 2019 Nov 26; 29(9):2672-2688.e7

PMID

31775037

DOI

https://doi.org/10.1016/j.celrep.2019.10.110

Grant

CA034196,CA045508,CA1728206,KG091029,66810101, JAX start-up funds

Abstract

Misregulation of alternative splicing is a hallmark of human tumors, yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer and uncover differences and redundancies in their targets and biological functions. We identify splicing factors frequently altered in human breast tumors and assay their oncogenic functions using breast organoid models. We demonstrate that not all splicing factors affect mammary tumorigenesis in MCF-10A cells. Specifically, the upregulation of SRSF4, SRSF6, or TRA2β disrupts acinar morphogenesis and promotes cell proliferation and invasion in MCF-10A cells. By characterizing the targets of these oncogenic splicing factors, we identify shared spliced isoforms associated with well-established cancer hallmarks. Finally, we demonstrate that TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival.

Comments

We thank J.E. Wilkinson for assistance with histopathology, S. Sampson and T. Helenius for comments on the manuscript, and M. Yurieva for assistance with GEO submission. We acknowledge assistance from The Jackson Laboratory (JAX) and Cold Spring Harbor Laboratory (CSHL) Microscopy and Sequencing Shared Resources.

This article is available under the Creative Commons CC-BY-NC-ND license.

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