Scientists identify molecular link between estrogen receptors and invasive growth in breast cancer

April 17, 2003

ATLANTA--Emory University and Winship Cancer Institute scientists have discovered a link between estrogen receptors -- the molecules that bind the estrogen hormone to cells -- and invasive growth of breast cancer. The finding could help explain the mechanisms leading to breast cancer progression and could have important consequences for drugs that are aimed at blocking estrogen receptors. The research is published in the April 18 issue of the journal Cell.

The research was conducted in the laboratory of Paul A. Wade, PhD, assistant professor of pathology and laboratory medicine in Emory University School of Medicine. Lead author was Naoyuki Fujita, PhD, Emory pathology postdoctoral fellow, and other investigators included Emory pathologists David L. Jaye, MD, Masahiro Kajita PhD, Cissy Geigerman, and Carlos S. Moreno, PhD.

Estrogen receptors regulate normal breast cell growth and development. The presence or absence of estrogen receptors in breast cancer patients is a critical prognostic indicator of breast cancer progression. Approximately 70% of breast tumors contain estrogen receptors and are dependent on estrogen for their growth. These breast cancers -- called "estrogen receptor positive" tumors ---- are routinely treated or prevented by a class of drugs known as selective estrogen receptor modulators (SERMS), including drugs such as tamoxifen, which block the estrogen receptors. Breast tumors lacking estrogen receptors -- called "estrogen receptor negative" tumors -- are not affected by estrogen antagonist drugs, and thus generally have a much less favorable prognosis.

In seeking the genetic alterations that cause breast cancers to lose their dependence on estrogen receptors for growth (becoming estrogen receptor negative), the Emory scientists discovered that a protein called MTA3 is part of an estrogen-dependent pathway that regulates the expression of other "downstream" molecules, including the cell adhesion molecule called E-cadherin. Cell adhesion molecules are responsible for maintaining normal cellular structure, and the loss or underexpression of these molecules has been associated with invasive growth of breast cancer. The investigators found that although MTA3 was active in the presence of estrogen receptors, in the absence of estrogen receptors MTA3 was not expressed and the MTA3 pathway failed to function, causing the repression of other molecules, including E-cadherin. In clinical samples of breast cancer tissue, the scientists found that tumors containing estrogen receptors expressed MTA3 and E-cadherin, while tumors without estrogen receptor did not.

"Our findings have important consequences for the treatment of patients with drugs that target the estrogen receptor, and they provide a mechanistic explanation for a pathway that may lead to cancer progression," said Dr. Wade. "A number of compounds currently in clinical trials for breast cancer, osteoporosis and other disorders target the estrogen receptor and turn it off in particular cells and tissues. Understanding how these compounds affect the estrogen receptor pathway and the potentially negative results from loss of the proteins that regulate cellular architecture, is very important in assessing the safety of these drugs and in developing other effective therapies for breast cancer."
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Emory University Health Sciences Center

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