NEW NUCLEAR MATRIX PROTEIN IN BREAST CANCER GROWTH

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DESCRIPTION (Applicant's Description): The candidate's research experience is in the field of breast cancer. During her postdoctoral work she was able to show that heat shock proteins (specifically hsp27) play an important role in growth and drug resistance. She therefore decided to study the transcriptional regulation of hsp27, with the final goal of identifying a factor which could be used to manipulate hsp27 levels in breast cancer cells. During these studies she cloned a novel protein (HET) which apparently is identical to a recently cloned scaffold attachment factor/nuclear matrix protein. During the last year the candidate started analyzing HET and found that HET indeed is a nuclear matrix protein, that it can bind to matrix attachment regions (MAR), and that it acts as a transcriptional repressor. Furthermore, HET has many tumor suppressor-like c h a r a cteristics, including inhibition of tumor growth and loss of heterozygosity at its chromosomal locus. Her results soon made it clear that although HET was originally identified as an hsp27 promoter binding protein, i t m a y have many more important functions, which warrant further investigation. The proposed studies are based upon these findings, and they now define an area of interest for the candidate which is separate from that of her colleagues, but allows her to draw from the expertise she has gained during her postdoctoral work in the Division of Medical Oncology. The candidate would obtain additional training during years 1 and 2 from sponsor Dr. Kent Osborne, who is an expert in translational breast cancer research. By Year 03, the candidate will be a fully independent investigator. The goal of the proposed studies is to characterize HET's effect on breast cancer growth, and identify possible mechanisms (e.g. identification of HET target genes which might be involved in cell cycle regulation). This study will provide new insight into basic mechanisms of breast cancer growth, and may ultimately lead to new therapies by targeting a nuclear matrix protein critical in tumor growth.