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Researchers decode breast cancer mystery

by Ruth SoRelle, MPH

C. Kent Osborne, MD

Tamoxifen has proven an important tool in the fight against breast cancer in women who have already undergone treatment for the disease. In some, it prevents the original breast cancer from coming back and stops the development of new tumors in the other breast.

However, it does not work for everyone. Now C. Kent Osborne, MD, and Rachel Schiff, PhD, both with the Breast Center at Baylor College of Medicine in Houston, think they may know why.

A previously unrecognized collaboration of genes, receptors and growth factors in the cells of these patients whose tumors are resistant can change tamoxifen from a tumor-inhibitor to a tumor growth factor. Schiff and Osborne revealed their finding in a recent report that appears in the Journal of the National Cancer Institute.

In breast cancer cells, tamoxifen works as an anti-estrogen, preventing the hormone from entering the cells. That is beneficial because it stops the cancer-promoting action of the hormone. Estrogen can promote the growth of breast cancer cells that contained receptors for it. These cancers are known as estrogen-receptor positive tumors.

When given to patients who have or have had breast cancer, tamoxifen can actually slow or stop the growth of the cancer cells that are already in the body. It can also prevent new cancers from forming in the other breast.

Not for everyone

The mystery of why some estrogen-receptor positive cancers do not respond to tamoxifen lies in the estrogen receptor itself and its relationship to other receptors on the membrane of the cell.

Treating those particular breast cancers with new drugs that target and block that collaboration or pathway may restore the tumor-fighting potential of tamoxifen in these cancers, said Osborne, BCM professor of medicine and molecular and cellular biology and director of the Breast Center at Baylor College of Medicine and The Methodist Hospital.

‘I’m excited because it is based on biologic principles,” said Osborne. “It ought to work in some patients, specifically those in whom these gene pathways are active.”

The tumors most resistant to tamoxifen are those that contain not only estrogen receptors but also an overabundance of another growth factor receptor called HER2/neu and a molecule that activates the estrogen receptor called AIB1. Other studies suggest that some estrogen receptors may be located in the membrane, close to HER-2.

“Tamoxifen binds to the estrogen receptor in those cells and instead of antagonizing it, it activates it. It acts like estrogen,” said Osborne. He and his coworkers postulate that in some cases, tamoxifen stimulates these tumors to grow and in others the hormone loses its ability to inhibit tumor growth in this subset of breast cancers.

When estrogen or tamoxifen binds to the estrogen receptor in the membrane, that receptor activates HER2/neu also found in the membrane.

“If you have a tumor with lots of estrogen receptor and HER2/neu in the membrane, adding tamoxifen to those cells is like adding a growth factor. The estrogen receptor gets activated and that activates the growth factor pathway which then further activates the estrogen receptor. You get this vicious cycle stimulating the tumor cells to survive and proliferate,” said Osborne.

Blocking the pathway

Using a drug to block the growth factor pathway, however can totally reverse this effect, allowing tamoxifen to assume its role as a tumor fighter once again, he said.

“This new treatment approach of combining tamoxifen and other forms of hormonal therapy with an inhibitor of the growth factor pathway is now being tested in patients with breast cancer in clinical trials ongoing in our Breast Center at Baylor College of Medicine and The Methodist Hospital and several other institutions around the world,” he said.

Others who participated in the study include Drs. Jiang Shou and Suleiman Massarweh, BCM researchers. Dr. Alan E. Wakeling is associated with AstraZeneca in Macclesfield, United Kingdom and Dr. Simak Ali is with the Imperial College of Science, Technology and Medicine in London.

This research was supported by a Breast Cancer Spore Grant from the National Cancer Institute and NCI grant P50 CA058183 (Breast Cancer SPORE Grant) and in part by a grant from AstraZeneca.

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