Research connects specific variations in RNA splicing with breast cancer causation

Research connects specific variations in RNA splicing with breast cancer causation
Krainer and colleagues 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 analyzed here. Credit: Krainer Lab, CSHL

Researchers have identified cellular changes that may play a role in converting normal breast cells into tumors. Targeting these changes could potentially lead to therapies for some forms of breast cancer.

In work published today in Molecular Cell, a team of researchers led by Professor Adrian Krainer at Cold Spring Harbor Laboratory (CSHL) analyzed the effects of overexpressing a cancer-promoting protein called SRSF1 in both a cellular model of breast cancer and in human breast tumors, and identified changes that could be responsible for SRSF1's ability to cause cancer.

SRSF1 is a factor, a type of protein that plays a crucial role in the process by which genes give rise to proteins. Splicing factors such as SRSF1 help edit the coded "message" copied from genes. These copies of the gene's message, called transcripts, are made of RNA. Splicing literally snips out parts of the message - called introns - that don't encode protein; and they paste together the remaining portions of the message - called exons - that do encode protein.

SRSF1 and other splicing factors can also direct a related process called —the mixing and matching of different exons from one gene, which, when spliced together, give rise to variant versions of a single protein, ones that often have very different functional properties.

"Long ago we and others saw that the levels of splicing proteins are altered in various cancers," says Krainer. "Previous work indicated that there are lots of alterations in splicing in the context of cancer," he says.

SRSF1 was previously shown to be an oncoprotein, i.e., a protein involved in cancer. When it is overexpressed, it can help convert normal cells into tumor cells. Krainer decided to examine its role in breast cancer "because we see frequent overexpression of SRSF1 in breast tumors," he says.

Experiments conducted by Olga Anczuków and Martin Akerman, co-first authors of the new paper, other colleagues in the Krainer lab, and their collaborators at the ETH in Zurich, demonstrated how overexpression of SRSF1 in a cellular model of breast cancer resulted in changes in the RNA messages generated in the cells. This allowed the team to pinpoint the splicing targets regulated by SRSF1, and gave them a glimpse of the SRSF1-related changes in those cells.

The team identified and validated hundreds of alternative splicing events regulated by SRSF1. They also looked at data from The Cancer Genome Atlas, identifying alternative splicing events associated with SRSF1 overexpression in human breast tumors. "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," explains Anczuków.

Based on the overlap between SRSF1 overexpression data in breast cancer cell lines and human , the researchers identified a candidate gene called CASC4. Overexpressing one alternatively-spliced form of the CASC4 protein partially mimicked the effects of overexpressing SRSF1, suggesting that CASC4 contributes to SRSF1's oncogenic effects. Krainer says CASC4 is likely to be just one of many targets that explain SRSF1's ability to cause cancer, and several targets probably act in concert to produce all the oncogenic changes related to SRSF1 overexpression.

Identifying the key oncogenic alternative splicing events caused by SRSF1 and other splicing factors could lead to potential therapeutic targets for treating . "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," says 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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More information: "SRSF1-Regulated Alternative Splicing in Breast Cancer" appears online in Molecular Cell on October 1, 2015. The authors are: Olga Anczuków, Martin Akerman, Antoine Cléry, ..., Yimin Hua, Frédéric H.-T. Allain, Adrian R. Krainer. The paper can be obtained online at:
Journal information: Molecular Cell

Citation: Research connects specific variations in RNA splicing with breast cancer causation (2015, October 1) retrieved 20 September 2019 from
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Oct 01, 2015
Virus-perturbed nutrient energy-dependent protein folding biochemistry has been repeatedly linked to different types of cancer via RNA-mediated events, but rarely are viruses linked to cancers.

This is an example of an unexplained theoretical link that has been explained by what is currently known about links from top-down causation via physics, the chemistry of protein folding, and the molecular mechanisms of RNA-mediated amino acid substitutions that stabilize organized genomes in all living genera.

Until medical practitioners focus more attention on the molecular mechanisms of healthy longevity, the ignorance of theorists will continue to contribute to suffering and death via virus-perturbed protein folding that evolutionary theorists link to beneficial mutations and evolution.

Oct 01, 2015
This news report is linked to a report on "Overexpression of splicing protein in skin repair causes early changes seen in skin cancer"

See also: Study: Vitamin B3 may help prevent certain skin cancers http://medicalxpr...ers.html

This news report is also linked to "Study reveals details of alternative splicing circuitry that promotes cancer's Warburg effect"

However, each time I provide a link to the creationist literature on virus-driven pathology, the moderators here remove the post and claim that the reason they removed it is because it was PSEUDOSCIENCE.

They also threaten to ban me if I continue to provide the links, but I suspect I will be banned anyway. Mainstream science is currently mostly pseudoscientific nonsense based on evolutionary theory. Serious scientists are Combating Evolution to Fight Disease. http://www.scienc...88.short

Are there any serious scientists here?

Oct 01, 2015
http://medicalxpr...ers.html Study: Vitamin B3 may help prevent certain skin cancers

If the moderators link to this report, could they be accused of linking to PSEUDOSCIENCE?

I ask because it was a young earth creationist who alerted me to the link from vitamin B3 to skin cancer.

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