Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis

Park, S., Brugiolo, M., Akerman, M., Das, S., Urbanski, L., Geier, A., Kesarwani, A. K., Fan, M., Leclair, N., Lin, K. T., Hu, L., Hua, I., George, J., Muthuswamy, S. K., Krainer, A. R., Anczukow, O. (November 2019) Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis. Cell Rep, 29 (9). 2672-2688.e7. ISSN 2211-1247 (Public Dataset)

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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 TRA2beta 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 TRA2beta is regulated by the MYC oncogene, plays a role in metastasis maintenance in vivo, and its levels correlate with breast cancer patient survival.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment diseases & disorders > neoplasms diseases & disorders > cancer > cancer types > breast cancer Investigative techniques and equipment > cell culture > cancer organoids bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > splice site
CSHL Authors:	Krainer, Adrian R. Akerman, Martin Das, Shipra Fan, Martin Lin, Kuan-Ting Hu, Leo Hua, Ian Muthuswamy, Senthil K. Anczukow, Olga
Communities:	CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL labs > Krainer lab CSHL Cancer Center Shared Resources > Animal Shared Resource
Depositing User:	Adrian Gomez
Date:	26 November 2019
Date Deposited:	18 Dec 2019 17:37
Last Modified:	02 Feb 2024 20:07
PMCID:	PMC6936330
Related URLs:	Publisher
Dataset ID:	GEO: GSE137440 GEO: GSE137408 ChIP-Seq datasets: https://www.encodeproject.org/.
URI:	https://repository.cshl.edu/id/eprint/38790

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