Apr. 3, 2008 Millions of post-menopausal women use hormone replacement therapy (HRT) as a method to reduce symptoms associated with menopause. In a recent University of Missouri study, researchers found that one of the hormones used in HRT, a synthetic progestin, could be a major factor in promoting breast cancer. At the same time, the researchers have compelling evidence that using an antibody that prevents new blood vessel formation in tumors, or a small molecular drug, known as PRIMA, with similar properties as the antibody may be effective in treating or preventing the negative effects of progestin.
In a study published in the journal, Cancer Research, MU scientist Salman Hyder and his research team found that exposing tumor cells to progestin caused an increase in a growth factor that is involved in the formation of new blood vessels in tumors. Increasing the blood supply allows the tumors to expand as the availability of nourishment increases. However, when they used an antibody that inhibits the growth factor, the tumor shrank. Hyder's team found similar results using PRIMA, which re-activated a protein known as p53. When p53 was activated within tumor cells, the number of breast cancer cells reduced significantly.
"As women age, many develop tiny lesions in their breasts," said Hyder, professor of biomedical sciences in the College of Veterinary Medicine and the Dalton Cardiovascular Research Center. "The majority of the time, these lesions never expand. We think this might be due to a specific protein, p53, that, under normal circumstances, prevents tumor cells from living. We found in our study that when the protein is active, it reduces the number of breast cancer cells in the body by inhibiting the growth factor that supplies blood vessels to the tumor. However, when the cells of these lesions are exposed to progestin in a body that does not have an active p53 protein, we found that the cells might start expanding and turn into tumors."
The synthetic progestin Hyder's team studied is known as medroxyprogesterone acetate (MPA), which is commonly used in HRT. Using an animal model, Hyder introduced MPA to the animals that were carrying human breast cancer cells. When the breast cancer cells were exposed to MPA, they began growing at an accelerated rate. Later, when the research team exposed the cells to the antibody known as 2C3, or PRIMA -- both of which block formation of new blood vessels in tumors -- the tumor cells failed to grow and spread in response to the MPA.
"Since MPA is a synthetic hormone, it stays in the body longer," Hyder said. "Unfortunately, while the drug is used to protect the uterus from the harmful effects of estrogens in HRT formulations, it is hurting the breast."
The Women's Health Initiative estimated a 26 percent jump in the number of breast cancer cases among women ingesting estrogen and progestin. Hyder believes that a large number of these women might also have a p53 protein that is not active and, therefore, not able to inhibit MPA-induced growth factor that helps to proliferate the tumor cells. Hyder cautioned that these studies are at an early stage and a lot of work remains to link progestin use firmly with progression of breast cancers in women.
Hyder, who also is the Zalk Endowed Professor of Tumor Angiogenesis, was assisted in the study by Yayun Liang, research assistant professor of biomedical sciences, Cynthia Besch-Williford, associate professor of veterinary pathobiology, and Rolf Brekken, assistant professor of Therapeutic Oncology and Surgery at the University of Texas Southwestern Medical Center.
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