The Role of the EGF Receptor First Intron in Its Regulation in Breast Canceer.
Final rept. 1 Sep 94-31 Jul 97
GEORGETOWN UNIV WASHINGTON DC
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Hormone independent human breast cancer is characterized by estrogen receptor ER loss and the acquisition of high epidermal growth factor receptor EGFRlevels. Despite the tendency for an inverse correlation between EGFR and ER, EGFR is a strong prognostic indicator for poor survival rate independent of ER status suggesting that EGFR overexpression is an important step in the progression to estrogen independence. Our studies have shown that several DNase I hypersensitive sites which correspond to potential regulatory protein binding sites reside within the EGFR gene first intron exclusively in hormone independent breast cancer cells, and micrococcal nuclease assays indicated that a disrupted and shifted nucleosome phasing pattern of the EGFR first intron occurs in a high EGFR expressing cell line. CAT assays demonstrated that a l40bp region of the first intron of EGFR has enhancer ability specifically in these hormone independent breast cancer cells. The DNA-protein interaction that occurs in this region was localized to a 35bp fragment that retains enhancer activity, and potentially to the sequence ATGACT. We hope that identifying the specific regulatory elements involved in EGFR up-regulation will assist in developing new therapies for preventing and treating aggressive, estrogen independent breast cancer.
- Medicine and Medical Research