Study finds long-term exposure to progesterone may lead to growth of tumors

Scientists at Michigan State University have found exposure to the hormone progesterone activates genes that trigger inflammation in the mammary gland.

This progesterone-induced inflammation may be a key factor in increasing the risk of breast cancer.

Progesterone is a naturally occurring steroid hormone and promotes development of the normal mammary gland. Progesterone previously has been identified as a risk factor for breast cancer, and in a study published in the Journal of Steroid Biochemistry and Molecular Biology, MSU scientists examined the genes activated by progesterone and the effects of their activation in a mouse model system.

Exposure to progesterone in normal amounts and in normal circumstances causes inflammation, which promotes breast development. However, exposure to progesterone in menopausal hormone therapy is known to increase breast cancer risk.

"Progesterone turns on a wide array of genes involved in several biological processes, including cell adhesion, cell survival and inflammation," said physiology professor Sandra Haslam, co-author of the paper and director of the Breast Cancer and the Environment Research Center at MSU. "All of these processes may be relevant to the development of breast cancer."

The study shows progesterone significantly regulates 162 genes in pubertal cells, 104 genes in adult cells and 68 genes at both developmental stages. A number of these genes make small proteins, called chemokines, which control the process of inflammation.

Inflammation is a process where white blood cells move into a tissue. One type of white blood cell which moves to the breast during inflammation is a macrophage. Macrophages normally enter growing glands and help them develop, building blood vessels and reshaping growing tissue.

"Macrophages also may promote the development of tumors, such as breast cancer, as they make blood vessels to deliver nutrients and can clear the way for tumors to grow," Haslam said. "Long-term exposure to progesterone, such as that which occurs in menopausal hormone therapy, may encourage growth of tumors."

Haslam noted that as the link between progesterone and increased breast cancer risk was identified in recent years, women have been taking less hormone therapy after menopause and the rate of breast cancer in older women has gone down.

"This study reveals the targets of a specific form of the progesterone receptor, called PRA, in mammary cell development," said microbiology professor Richard Schwartz, a co-author of the paper and associate dean in the College of Natural Science. "The linkages identified provide targets for future work in reducing the influence progesterone has on developing breast cancer.

"Understanding the genes that regulate inflammation in the mammary gland will help us to better understand normal breast growth and also may help us devise better treatments for the abnormal growth in cancer."

A collaborative team of 10 scientists in MSU's departments of Physiology and Microbiology and Molecular Genetics contributed to the findings. The team's work was published in the July 2009 issue of the journal.

The team of faculty is part of MSU's Breast Cancer and the Environment Research Center, one of four centers nationwide funded by the National Institute of Environmental Health Sciences and the National Cancer Institute. The center brings together researchers from MSU's colleges of Natural Science and Human Medicine to study the impact of prenatal-to-adult environmental exposures that may predispose a woman to breast cancer, as well as researchers in the College of Communication Arts and Sciences to study how to best communicate breast cancer health messages to the public.