The cell-based study suggests that a small-molecule therapeutic called TPBM and related compounds are likely to be effective against breast cancers that depend on estrogen to grow (called estrogen receptor-positive) but that are resistant to current therapies, team leader David Shapiro, PhD, said.

Shapiro, a biochemist at the University of Illinois at Urbana-Champaign, said at detection, about two-thirds of breast cancers are estrogen receptor-positive, and virtually all of these cancers become resistant over time to the breast cancer drug tamoxifen. In some tamoxifen-resistant tumors, tamoxifen begins to act like estrogen and can actually stimulate tumor growth, he explained.

Therefore, researchers are trying to find new ways to block resistance to drugs such as tamoxifen. Shapiro's team developed a technique to screen for chemical compounds that would inhibit the ability of estrogen and the estrogen receptor protein to bind to DNA and turn on gene expression in breast cancer cells.

"We targeted a different step in the pathway of estrogen action, one that is not targeted by current therapeutics," Shapiro said.

They then tested various agents in estrogen receptor-positive breast cancer cells in the laboratory. The team identified a family of compounds related to TPBM that Shapiro said inhibited the estrogen-dependent growth of breast cancer cells.

"TPBM is highly targeted and has little or no toxic effect on other cells-those that don't depend on the estrogen receptor," Shapiro said. "Also important, these compounds are effective in breast cancer cells in which tamoxifen acts like estrogen."

Thus, these compounds might prevent tamoxifen-resistant breast cancer from becoming more aggressive. However, Shapiro cautioned that their research is in the early stage. A future step will be testing the new estrogen receptor inhibitors in animal models of breast cancer.

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"There is additional work to do to determine if the function of these genetic variants actually contributes to the development of type 2 diabetes or heart disease," she explains. "We do expect that a number of different changes, in both CD36 and other genes, will be related to these diseases. What we'd like to learn, however, is whether the changes identified in the gene alter the CD36 protein in ways that change its function to make a person more vulnerable."

The team determined that five of the SNPs they examined are more common in people who have symptoms of metabolic syndrome, but a sixth seemed to have a more favorable metabolic effect. The "protective" SNP makes people produce lower amounts of CD36 protein.

Humans have two copies of each chromosome. In this study, people who had the protective variant on only one of their copies of chromosome 7 were less susceptible to metabolic syndrome. But people with two copies of the variant, who were completely deficient in the CD36 protein, did not appear to be protected. They tended to have lower levels of HDL, the so-called good cholesterol.

"A bit less CD36 protein may improve your risk profile, but people need some CD36 function," Abumrad says. "It's like requiring a certain level of fat in the diet. Fatty acids are important for optimal function of many tissues - from pancreatic beta cells to skeletal muscle to the heart - but too much fat creates a problem."

Love-Gregory and Abumrad found that many variants influenced blood levels of HDL cholesterol. Now they are taking a closer look at the relationship between CD36 and HDL cholesterol. Higher levels of HDL normally are considered positive, but because changes in the CD36 gene seem to influence HDL, the researchers want to make sure that the HDL molecule isn't being altered in composition or function.

"We're going to follow up on the HDL component of the study," Love-Gregory says. "We're also going to look for additional variants in the promoter region of the gene that controls how the gene is regulated. And we're planning to look for evidence of these gene variants and their associations with HDL and the metabolic syndrome in other populations and ethnic groups."

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