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The Man Who Knows Too Much
The Culprit is Cancer

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Fall 1998
The Culprit is Cancer
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In 1982, Slamon submitted to NIH a grant proposal for funding to build a human tumor bank using discarded tissue from breast, prostate, colon and lung cancers and then screen the tissue for specific genetic alterations. "The application essentially came back with a laugh track," he recalls. Undeterred, Slamon and his team secured support from the Jonsson Cancer Center Foundation and UCLA and forged ahead with the human tumor bank plan.

In the meantime, academic and commercial labs across the country were isolating new genes. In 1986, a scientist at MIT discovered an important gene involved in regulating cell growth. It was HER-2/neu - Human Epidermal Growth Receptor No. 2.

Slamon was by now convinced of the logic of his approach, but many of his peers remained dubious. " 'Oh, this lab is on a fishing expedition,' " Slamon recalls his critics saying. "Well, we were fishing for alterations that we might identify. But we felt that once we identified one, we had the capacity to do the harder work of pulling out the gene and introducing it into breast cancer cells to see if it really had an association with a bad outcome. That was the most exciting science of all. As soon as we had valid models, we could start testing."

Using breast cancer tissue, Slamon and his team began extracting DNA and asking questions: Was the HER-2/neu gene changed? Was its structure somehow rearranged? Was its expression present in some altered way?

Indeed it was. Instead of the single copy of HER-2 normally present in a cell, Slamon found multiple copies in approximately 30 percent of breast cancer samples. "This gene makes something called a growth factor receptor," he explains. "It's a protein that sits like an antenna on the membrane of the cell and receives signals from the outside telling the cell to grow."

Slamon then looked at women who had the genetic alteration to see if tumors they developed were in any way unusual compared to tumors of women without HER-2. Sure enough, women with the alteration had far more aggressive disease: They failed standard therapy, their disease metastasized more quickly, they died sooner.

Slamon was hopeful, but he hadn't yet proved that HER-2 was causing the cancerous cells to multiply out of control. The alteration might only be a marker, what scientists call an epiphenomenon, that develops along with the real culprit driving the cancer.

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