ACTR/A1B1 in Mammary Gland Development and Tumorigenesis

Institution: Salk Institute for Biological Studies
Investigator(s): Wen Xie, M.D., Ph.D. -
Award Cycle: 1999 (Cycle V) Grant #: 5FB-0117 Award: $16,178
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (1999)
Most breast cancer arises from the uncontrolled growth of mammary epithelial cells. The steroid hormone, estrogen, stimulates the growth of mammary epithelial cells. Estrogen is required for the normal growth of the breast and is a prerequisite for breast cancer formation. Blocking of estrogen receptor or estrogen action results in tumor regression in breast cancer patients with hormone-dependent tumors. Recently, a group of proteins called "nuclear receptor co-factors" has been identified that play a central role in regulating the function of steroid hormones and their receptors. ACTR/AIB1 (Amplified in Breast Cancer-1), a nuclear receptor coactivator, interacts with the estrogen receptor and enhances the biologic effects of estrogen. In addition, overproduction of ACTR/AIB1 has been found in breast cancers and in human breast cancer cells lines. ACTR/AIB1ís ability to enhance the function of estrogen receptor in addition to its overproduction in breast cancer implicate ACTR/AIB1 as an important player in estrogen response and as a potential contributor to the initiation and progression of breast cancer. In order to determine the significance of ACTR/AIB1 in breast cancer, it is necessary to investigate the biologic effects of ACTR/AIB1 in animal models.

To examine the role that ACTR/AIB1 plays in the control of breast development and breast cancer formation, we will generate transgenic mice in which ACTR/AIB1 is particularly overproduced in the breast. We will perform experiments to examine: 1) the changes in the development of the breast as the result of overproduction of ACTR/AIB1; 2) whether the overproduction of ACTR/AIB1 is sufficient to cause breast cancer; and 3) whether ACTR/AIB1 can accelerate breast cancer formation by other known cancer-causing agents. The results of these experiments will enhance our understanding of normal breast development and of breast cancer pathogenesis. Furthermore, if ACTR/AIB1 is proved to promote the formation of breast cancer, blocking ACTR/AIB1 signaling might be a useful strategy in developing novel therapies for breast cancer.

Constitutive activation of gene expression and binding of coactivators by estrogen related receptor 1 and 2. SALK/EMBL Oncogenes and Growth Control The Salk Institute, La Jolla, California, August 1999.
Periodical:Molecular Endocrinology
Index Medicus: Mol Endocrinol
Authors: Xie, W., Heng, H. Yang N., Lin, R.J., Simon, C.M., Stallcup, M.S. and Evans, R.M.
Yr: 1999 Vol: 13 Nbr: Abs: Pg:2151-2162