Illinois Medicine

Stopping Cancer Before It Grows C OLLEGE OF MEDICINE RESEARCHERS have made two separate discoveries that could provide important clues into what causes tumors to grow—and how to stop them. The first study, which resulted from an international collaboration with Spanish researchers and was published in the online journal Genes and Development, has shown that inactivation of two pathways that inter- act to regulate cell division profoundly disrupts cell-cycle control and causes tumors to grow. One of these critical pathways regulating the cell cycle is the retino- blastoma tumor suppressor pathway, which is mutated or functionally inac- tivated in almost all human cancers. Maxim Frolov, PhD, associate professor of biochemistry and molecular genet- ics, studies inactivation of Rb in fruit flies, which by itself does not cause a full-blown tumor. "We wanted to un- derstand why," says Frolov, whose lab collaborated with Nuria Lopez-Bigas' genomics group at the University of Pompeu Fabra in Barcelona. Frolov and his colleagues believed other regulatory pathways could be working together with the Rb pathway, and they focused on a pathway called Hippo, which seemed to work with Rb in regulation of cell proliferation in their previous studies. Their hypothesis that inactivating both pathways simultaneously would grow tumors proved correct. The researchers found that inac- tivating the Hippo and Rb pathways results in an up-regulation of a unique set of genes, creating the synergy between these two pathways. "We saw that the genes important to cell proliferation and cell cycle regu- lation are inappropriately expressed in these cells," Frolov says. "We found that transcription factors—proteins that turn genes on and off—involved in each of the two pathways cooperate in inducing expression of these cell-cycle specific genes, resulting in inappropri- ate cell proliferation." The Hippo-Rb synergy may have important implications for understanding the complexity of mutations in human cancers, Frolov says. "We should be looking for more cooperating mutations in human cancers," he explains. The study received funding from the National Institutes of Health, the Catalonian government and the Leuke- mia and Lymphoma Society. Separately, researchers under the direction of Geula Gibori, PhD, profes- sor of physiology and biophysics, have found an enzyme that produces a po- tent form of estrogen in human breast cancer tissue, which, in turn, produces more of the enzyme. The extra-strength estrogen, called estradiol, has been implicated in exac- erbating breast cancer tumor growth, according to the research published in the May issue of the journal Mo- lecular Endocrinology. Scientists had observed that estrogen increases the production of an unknown protein in ovarian tissue; researchers then puri- fied the protein and cloned its gene. "Estradiol up-regulates the very enzyme that produces estradiol, creating a positive cycle where this potent form of estrogen is being pro- duced over and over again, sustain- ing its own production," says Aurora Shehu, PhD '08, a second-year medi- cal student and postdoctoral research associate in physiology and biophys- ics and first author of the study. Researchers found a dramatic up-regulation in the cancerous breast tissue cells but not in the surrounding benign tissue, says Gibori, principal investigator, but that benign tissue is a rich source of the estrone that the enzyme needs to produce more estradiol. The researchers demonstrated how estradiol turns on the gene that produces the enzyme and found that tamoxifen, a drug commonly used to limit growth of breast cancer, stops estradiol's stimulation of the enzyme— and thus may have the effect of shut- ting down local production of estradiol in breast cancer cells. "Breast cancer tumors with this enzyme are likely to be a much more aggressive and potentially deadly type of cancer," Gibori says. "Identifying this enzyme and how its expression is turned on gives medical researchers potential targets for disrupting the lethal production of estradiol in breast cancers." Blocking the enzyme might stop only the dangerous estradiol, reducing the side effects common with other drugs that fight against estrogen-related compounds, Gibori says. Studies of pathways and enzymes offer insights into tumor growth ILLINOIS MEDICINE | 9

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