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    Awarded Grants
    The Differential Effects of Estrogen on Gene Regulation and Apoptosis in the Breast and Bone

    Scientific Abstract:
    Estrogen plays a biological role in the mammary gland, ovaries, brain, heart, and bone, among other tissues. The molecular mechanism of estrogen action in the bone, however, is not well studied. The aims of this proposal are designed to understand gene regulation by estrogen, and to understand why there are different biological effects of estrogen in different tissues, which is of key importance for anti-estrogen and estrogen deprivation therapies for patients with breast cancer. Estrogen is known to promote growth in mammary epithelial cells, but to cause apoptosis in osteoclasts. While this phenomenon has been noted for years, the mechanistic basis of this difference is not understood. My first aim is to determine how apoptosis is occurring in osteoclasts in response to estrogen, and to specifically look at which pathways are involved, including which caspases are activated. Secondly, I propose to look at the pattern of gene regulation by estrogen in osteoblasts, osteoclasts and mammary cells by microarrays and chromatin immunoprecipitations. My third aim is to develop a mouse model of oncolytic metastasis using an AIB1 transgenic mouse developed in my laboratory. Taken together these experiments will provide valuable information for the treatment of breast cancer (including oncolytic metastasis) and osteoporosis.

    Lay Abstract:
    Breast cancer will affect one in eight women during their lifetime. A large percentage of breast cancers depend on the presence of estrogen to grow, and are classified as “estrogen receptor positive”. Thus, women are treated with drugs that block estrogen from working or lower estrogen levels, to prevent the tumor from growing. However, estrogen is necessary for the prevention of osteoporosis, among other functions. Normal bone is maintained by a balance of bone forming cells (osteoblasts) and bone destroying cells (osteoclasts). Osteoporosis occurs when there is an imbalance between bone formation and bone destruction. It is imperative to understand how the same hormone, estrogen, can cause some cells (breast cells) to grow and some cells (osteoclasts) to die. We hypothesize that there are tissue-specific factors that account for the differences in the expression of certain estrogen-regulated genes in bone and breast tissue. The experiments described herein are designed to explore the mechanism of how/why osteoclasts die in the presence of estrogen and to determine what genes are “turned on or off” by estrogen in the bone, but not in the breast. Furthermore, we will attempt to determine how breast cancer metastases degrade bone. In over 70% of advanced breast cancers there is metastasis to the bone, causing extreme pain, fractures and other problems. Very few models exist to study bone metastasis in mice, and therefore we propose to establish a mouse model to study breast cancer metastasis to bone. By understanding the biology of estrogen, in addition to establishing a metastasis model described in this proposal, we will be able to better treat women with breast cancer by understanding drug therapies and preventing metastasis.