Scientists analyzing human breast tumors have discovered that the tumors produce large amounts of a "fetal" form of a protein that can spur 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. The protein is one form of the insulin receptor. Its other -- "adult" -- form is a crucial part of the pathway that lowers blood sugar.
Until now, it was assumed that in tumors, insulin primarily linked up with its adult receptor 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.
"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, MD, professor of medicine and physiology at the University of California San Francisco 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.
"We're not saying that the insulin receptor causes breast cancer," he stressed, "but it is possible that it aids or stimulates tumor growth once the tumor has been established."
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 a related growth factor known as IGF-II. It is when the fetal form docks with insulin or IGF-II that rapid cell division ensues, stimulating cancer growth, the researchers found.
"In the breast tumors, the fetal form binds to both insulin and to IGF-II to stimulate tumor growth," said Goldfine. "Because of this process, the fetal form of the insulin receptor now appears to be a clear target for drugs to block or slow breast tumor growth."
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 and two laboratories in Italy. Senior author on the paper in Molecular and Cellular Biology is Riccardo Vigneri, MD, professor of medicine at the University of Catania. Senior author on the paper in Oncogene is Antonio Belfiore, MD, at the same institution. The laboratory of Paolo Sbraccia, MD, at the University of Rome also played a key role.
Co-authors on both papers, along with Goldfine, Vigneri and Belfiore, are Franceso Frasca, MD, Giueseppe Pandini, MD, Pierluigi Scalia, MD, Laura Sciacca, MD, Rosanna Mineo, MD, Angela Constantino, MD, all of University of Catania. Pablo Sbraccia, of the Unviersity of Rome is co-author only on the Oncogene paper.
The above story is based on materials provided by University Of California, San Francisco. Note: Materials may be edited for content and length.
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