A Trail of Breadcrumbs

When a fusion gene is seen repeatedly in a particular type of tumor, it suggests, but doesn’t prove, that the resulting fusion protein alone can drive tumor growth. It’s good news if it does, though, because Gleevec-like drugs that block the activity of a driving fusion gene, such as tyrosine kinase, often stop the tumor.

But each fusion gene must be tested to see whether it drives cancer on its own or whether it needs backup. For example, cells engineered to express BCR-ABL or EML4-ALK become cancerous, and mice engineered to express the two fusion genes develop leukemia or lung cancer, respectively. But mice engineered to produce the most common prostate cancer fusion gene, TMPRSS2-ERG, do not develop prostate cancer, Sawyers says.

To discover what else might be needed to drive prostate cancer, Sawyers obtained 218 prostate tumors, about half of which harbored the TMPRSS2-ERG fusion gene and sequenced 157 genes from each that have been linked to prostate cancer. One short stretch of chromosome 3 was deleted in almost all the tumors with the TMPRSS2-ERG fusion. Three of the eight genes in that deleted segment have hallmarks of genes that suppress tumor formation, and the three may turn out to collaborate with ERG to cause prostate cancer. “It’s a trail of breadcrumbs, so we’ll see,” he says.

To stop gene fusions from causing cancer, it’s also important to understand how these hybrid genes form in the first place, says molecular immunologist Fred Alt, an HHMI investigator at Children’s Hospital Boston. First, DNA must break cleanly at two chromosome locations inside a single cell. Second, the ends of the broken DNA must be brought together and attached to create a chromosomal translocation. Third, cells with this translocation must outgrow normal cells. In 2007, Alt’s team reported in Nature that they’d found a cellular pathway that can perform the second step, attaching broken ends of unrelated genes on different chromosomes. In 2009, they reported, again in Nature, that this pathway generates recurrent translocations that correlate with lymphoma. The pathway may also promote cancer-causing translocations in other tissues, he says.

Two HHMI investigators, Chinnaiyan and Michael G. Rosenfeld, of the University of California, San Diego School of Medicine, have recently shown that testosterone signaling actually spurs translocations in the prostate. This hormone binds to a gene-activating protein called the androgen receptor, and the resulting complex helps regulate thousands of prostate genes, including TMPRSS2. Chinnaiyan suspected that, when it binds testosterone, the receptor brings the TMPRSS2 and ERG into proximity within the cell’s nucleus, creating an opportunity for them to trade segments.

Chinnaiyan’s team confirmed this hypothesis by adding testosterone to cultured prostate cells, then fragmenting their DNA with ionizing radiation. The TMPRSS2-ERG fusion was created only if testosterone was present, the researchers reported in Science in November 2009. The results could explain why the TMPRSS2-ERG fusions occur only in the prostate, the sole organ where testosterone plays a dominant role in coordinating cellular physiology, Chinnaiyan says. Rosenfeld’s team reported similar results in Cell in December 2009. They also detailed how the androgen receptor recruits two enzymes that help to cut and rejoin the DNA. By studying how translocations occur, “we want to understand and screen for drugs or approaches to mitigate and abrogate the events,” Rosenfeld explains.

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