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October 5, 2015

RNA Splicing Factor Linked with Causes of Breast Cancer

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    Scientists reveal details about how the protein SRSF1 can promote cancer, via its function as a regulator of alternative splicing of gene messages. One gene called CASC4, whose splice variants are regulated by SRSF1 and can promote breast cancer, is shown above. [Krainer Lab, CSHL]

    Purely by coincidence, but in a timely fashion to coincide with breast cancer awareness month, a collaboration led by scientists at Cold Spring Harbor Laboratory (CSHL) have identified molecular events that may play a pivotal role in the carcinogenesis of normal breast tissue.

    The researchers analyzed the effects of overexpressing an oncoprotein called serine/arginine-rich splicing factor 1 (SRSF1), in both a cellular model of breast cancer and within human breast tumors—identifying changes that may be responsible for SRSF1's ability to cause cancer.

    SRSF1 is a splicing factor that plays a critical role in the process by which genes give rise to proteins. Splicing factors such as SRSF1 edit pre-mRNA molecules by literally snipping out parts of the message (introns) that don't encode protein and pasting together the remaining portions of the message (exons) that do encode protein.

    Additionally, splicing factors like SRSF1 can direct a related process called alternative splicing, which combines different exons from a single gene, giving rise to variant versions of a single protein that often having very different functional properties.

    "Long ago we and others saw that the levels of splicing proteins are altered in various cancers," explained senior author Adrian Krainer, Ph.D., professor at CSHL. "Previous work indicated that there are lots of alterations in splicing in the context of cancer because we see frequent overexpression of SRSF1 in breast tumors."

    The findings from this study were published recently in Molecular Cell through an article entitled "SRSF1-Regulated Alternative Splicing in Breast Cancer."

    The investigators conducted experiments to demonstrate how overexpression of SRSF1 within a cellular model of breast cancer resulted in changes of RNA messages generated in the cells. This work allowed the team to home in on the splicing targets regulated by SRSF1 and enabled them to observe the SRSF1-related changes in those cells.

    Moreover, the researchers identified and validated hundreds of alternative splicing events regulated by SRSF1 and compared them with alternative splicing events associated with SRSF1 from data collected at The Cancer Genome Atlas.

    "We pay special attention to potential targets that overlap between all these different data sets, because it's a way of narrowing down or giving higher priority to targets that may play an important role," noted co-first author Olga Anczuków, Ph.D., senior fellow at CSHL.

    Once all of the data was analyzed the investigators identified a candidate gene called CASC4. Overexpression of one of the alternatively-spliced forms of the CASC4 protein partially mimicked the effects of overexpressing SRSF1, suggesting that CASC4 contributes to SRSF1's oncogenic effects. The researchers concluded that CASC4 is likely to be one of many targets that explain SRSF1's ability to cause cancer, and that several targets probably act simultaneously to produce all the oncogenic changes related to SRSF1 overexpression.

    "If we find that a particular change is really critical in tumor maintenance, then we could potentially develop therapies to restore the normal splicing pattern," stated Dr. Krainer. "It probably depends on there being a small number, ideally one, but maybe a couple of crucial targets that the tumors really depend upon."

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