The overall goal of this research is to investigate the hypothesis that dysregulated expression and function of Beta Protein 1 contributes to breast cancer pathogenesis. Dr. Berg cloned a novel homeobox gene called BP 1 based upon its ability to repress human [_-globin gene expression. Expression of BP 1 is highly restricted in normal tissues;however, data from our laboratory indicate that BP1 is overexpressed in hematopoietic cell lines and human immune cell cancers. In our more recent studies, increased BP 1 expression was detected in breast cancer cell lines and human breast cancer samples. Together these data suggest that BP 1 is a proto-oncogene. Most recently, we have initiated studies to examine the mechanism of BPl-mediated oncogenesis. Preliminary data support a regulatory role for BP1 in estrogen and retinoid signaling pathways. We plan to extend these preliminary results and further explore the interaction of BP 1 with nuclear hormone signaling pathways in breast cancer. Specifically, we will: 1) Determine whether BP 1 is expressed in benign breast tumors. 2) Study the effect ofBPl overexpression and BP1 antisense RNA on estrogen receptor _ gene expression in breast cells. 3) Functionally define the interactions of BP 1 and ER transcriptional complex proteins in normal and neoplastic breast tissue. 4) Determine the effect of all-trans retinoic acid, 9-cis retinoic acid, estradiol, and the histone deacetylase inhibitor trichostatin A on breast cancer cells that overexpress BP1 compared to control cells. 5) Utilize microarray technology to determine the gene expression profile of breast cancer cells that overexpress BP 1. I will design and conduct research at The George Washington University Medical Center, within the laboratory of Dr. Patricia Berg. I will also utilize the resources of the Genomics and Proteomics core facility directed by Dr. Tim McCaffrey. I propose to be trained by experienced investigators, namely Drs. Berg and McCaffrey, who will guide me during my transition from research trainee to independent molecular biologist. In addition, Drs. Schwartz, Fontana, and Ascensao will provide overarching scientific and career guidance and independent ongoing peer review. Finally, Dr. Schaffner will mentor my training in the responsible conduct of research.
