Making the Fight Against Breast Cancer Crystal Clear

Cancer Biology

 

Kendall Nettles, associate professor of cancer biology at Scripps Research, describes his latest advancement in understated terms. “If you had a glass of salt water and let it evaporate you would get salt crystals. Basically, this is what we are doing with receptor proteins – except now we can test hundreds of different compounds [as crystallizing agents] simultaneously.”

The implications of Nettles’s discovery, however, are not so understated. Previously, scientists were only able to test one crystallization compound at a time, otherwise a key section of the protein would misfold. The process was painstakingly slow, resulting in only a few crystal structures a year. The method that Nettles developed, however – a process he calls “parallel crystallization” – allows scientists to test multiple compounds against the receptor proteins to see which ones produce crystals. Furthermore, the process allows scientists to simultaneously crystallize whole classes of compounds and identify subtle structural features that might not be apparent with individual structures.

Nettles, who joined the faculty of our Florida campus in 2005, is focused specifically on small molecule ligands. These atoms or molecules that bind to a site on a target protein and trigger specific biological actions may be key targets for affecting certain physiological processes. His team is studying the interaction between small molecule ligands and nuclear receptors, which line the interior of cells and are responsible for sensing the presence of hormones. Working in concert with other proteins, nuclear receptors are powerful agents that regulate the expression of specific genes, thus controlling the development and metabolism of the organism. By better understanding the interaction between small molecule ligands and nuclear receptors like estrogen receptors, Nettles’s team hopes to discover ways that small molecule ligands can affect the biological processes that nuclear receptors have a role in regulating.

“Members of the nuclear receptor superfamily make excellent drug targets because they can be regulated by small molecule ligands, including steroids,” he explains. However, estrogen receptors are particularly tricky. “Drugs that target the estrogen receptor in patients with breast cancer have some undesirable side effects in other tissues. For example, tamoxifen therapy increases the risk of a patient developing uterine cancer.”

Not only is estrogen involved in breast and uterine cancer, but its anti-inflammatory properties make it a useful treatment for neurological and inflammatory conditions. “Steroid hormones like estrogen are anti-inflammatory,” Nettles explains. “For example, when estrogen levels rise during pregnancy, symptoms of inflammatory conditions like arthritis subside.”

The challenge has been to capitalize on estrogen’s anti-inflammatory properties without increasing the risk of breast or uterine cancer. Nettles’s team made a great stride in that direction when, using its new crystallization method, the scientists were able to identify the ligand formations that are selectively anti-inflammatory – that is, they don’t activate normal genetic pathways for growth in breast and uterine tissue.

The promise of Kendall Nettles’s research for estrogen-driven cancers is garnering attention. In presentations to the Komen Foundation and breast cancer awareness groups, Nettles has given women suffering from the disease a new hope. You, too, can give these women hope by making a gift in support of Nettles’s research today.

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