Role of IGF Receptor in Cancer Revealed

Scientists at the University of California San Francisco (UCSF) and two Italian universities have discovered that human breast tumors produce large amounts of the fetal form of insulin-like growth factor receptor (IGF II) that might be stimulating uncontrolled cancerous growth. The findings, published in part in the May issue of Molecular and Cellular Biology and in part in the May issue of the journal Oncogene, pinpoint a clear target for new cancer drugs, the researchers say. Turning off this unsuspected fetal form of the protein would rob tumors of a potent cancer growth stimulant.

Until now, it was assumed that in tumors, insulin primarily linked up with the adult receptor (insulin receptor or IR) to metabolize sugars and other nutrients. But the researchers found that in breast tumors, the principal form of the insulin receptor appears instead to be the growth-stimulating fetal form. In examinations of human breast cancer cells and human breast tumor specimens, the scientists discovered that the insulin receptor is present in two slightly different forms—small amounts of the familiar adult form which binds only insulin, and larger amounts of the fetal form which can bind either insulin or the growth factor known as IGF-II. When the fetal form docks with insulin or IGF-II, rapid cell division ensues, stimulating cancer growth, the researchers found.

"We have found that in these cancers, the insulin receptor largely reverts to its fetal stage, where its prime mission is to spur rapid cell division," said Ira D. Goldfine, professor of medicine and physiology at the UCSF and co-author of the two scientific papers. Many cancers are known to express fetal proteins, he added.

In addition to its value in developing new drug strategies to control breast cancer, the research finding may offer a more immediate message, Goldfine suggests. "Breast cancer has both genetic and lifestyle components," he says. "We know that both a sedentary lifestyle and obesity cause levels of insulin to rise excessively. This rise, in turn, activates insulin receptors. Now that we have found—to our surprise—that the fetal insulin receptor is overproduced in breast tumors, it would seem that women who are prone to develop breast cancer are at greater risk if they are sedentary or obese because they may have more insulin available to activate fetal insulin receptors."

The Molecular and Cellular Biology paper established that a shortened form of the insulin receptor, known as IR-A, is the fetal form, or growth-stimulating form, and that it is activated by the growth-inducing protein IGF-II. The Oncogene paper reported the group's discovery that the fetal form of the insulin receptor is "over-produced" in breast cancers, and that it is activated in breast tumors by IGF-II.

The research is a collaboration between UCSF's Goldfine, Riccardo Vigneri, and Antonio Belfiore; professors of medicine at the University of Catania; and Paulo Sbraccia of the University of Rome.

For more information: Ira Goldfine, Professor of Medicine and Physiology, University of California San Francisco, Box 1616 MZ, San Francisco, CA 94143. Tel: 415-885-7430 or 415-885-7729. Fax: 415-885-7724. Email: idg@itsa.ucsf.edu.