The long term goal of this research is to define the genes and events involved in each step leading to breast cancer. The actin cytoskeleton is a dynamic infrastructure vital to many cell activities, including shape, survival, motility, and growth. However, very little is known about specific details of its function in mammary epithelial cells (MEC). Gelsolin, a multifunctional actin-binding protein, is a primary regulator of the actin cytoskeleton, a modulator of several key signal transduction components, and a tumor suppressor in fibroblastic and epithelial cells. Dr. Asch has shown that gelsolin is absent or drastically reduced in 70% of human sporadic, invasive breast cancers and in 80-100% of rodent mammary carcinomas of viral, chemical, hormonal, and spontaneous origins. However, no mutations in the gelsolin gene have been detected. Gelsolin's loss is novel and important because, it is the only molecular defect shown to occur in the majority of breast malignancies in humans, mice and rats, regardless of etiology. The results point to loss of gelsolin as a fundamental event in mammary tumorigenesis. Moreover, studies of gelsolin null mice have revealed that lack of gelsolin impairs mammary gland development and differentiation. Together these data strongly suggest gelsolin is a potential suppressor of breast cancer. Accordingly, the hypothesis that gelsolin is a tumor suppressor in mammary epithelium, and its loss facilitates deregulation of MEC growth and acquisition of malignant behavior will be tested. The objectives are to determine: 1) the epigenetic mechanisms responsible for loss of gelsolin in breast cancers; 2) if restoring gelsolin expression in breast cancer cells will promote growth control and/or inhibit malignant behavior; 3) the mechanism of gelsolin's tumor suppressor activity i breast cells; 4) if susceptibility to chemically-induced mammary tumorigenesis is increased in mice lacking gelsolin and if its absence enhances mammary tumorigenesis in transgenic mice overexpressing the oncogene, cyclin D1. The results will be relevant to the majority of sporadic human breast cancers and may point to new strategies for preventing, interrupting, and treating this disease.
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