The need to treat high-risk primary tumors with specialized forms adjuvant therapy and the recognized association of c-erbB-2 overexpression with high-risk breast tumors are two developments that have served to re-focus our effort to develop better oncogene-related markers for breast cancer prognosis. Standard assays of c-erbB-2 overexpression (mRNA and p185erbB-2 protein) and DNA amplification may not measure the fundamental dysfunction of this oncogene in some breast cancers. Unlike c-erbB-2, increased tumor levels of estrogen and progesterone receptors (ER, PR) denote a less aggressive tumor type and more favorable patient prognosis. Like c-erbB-2, however, current receptor assays do not measure receptor function and fail to identify many patients who recur with hormonally unresponsive and incurable disease. We are developing new assays for abnormal c-erbB-2 and ER function that will identify primary tumors at highest risk for relapse. As well, we are measuring the incidence of oncogene abnormalities in specific breast cancer subsets that have been poorly studied to date: male breast tumors and noninvasive in situ carcinomas. Does increased c-erbB-2 amplification or overexpression explain the poor survival associated with male breast cancer? Is p185erbB-2 overexpression in situ cancers due to early transformation by c-erbB-2 gene amplification? To detect abnormalities related to c-erbB-2 function we will measure tumor levels of a transcriptional transactivator(s) that mediates the overexpression of c- erbB-2. As well, we will characterize the tyrosine-phosphorylated protein substrates of p185erbB-2 that represent the dysregulated signal transducing mechanisms used by c-erbB-2 as well as various other tyrosine protein kinase-related proto-oncogenes and growth factor receptors. We will also test anti-p185erbB-2 antibodies and antisense-erbB-2 oligomers against primary tumor cells grown in short-term culture to identify individual tumors that are dependent on dysregulated c-erbB-2 expression for their malignant growth. High-risk ER-positive tumors with abnormal receptor function will be identified by altered in vitro binding of tumor cell ER to its gene-specific estrogen response element (ERE). Lastly, the formation of these ER-ERE complexes will be correlated with aberrant tumor expression of the ER-dependent stress-response protein, srp-27, and rate of clinical recurrence to determine how well these parameters identify patients at higher risk for relapse.
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