ACTIVATION OF ONCOGENES AND RECEPTORS IN HUMAN BREAST CANCER--ETS AND HER2/NEU

需要用专门的形式辅助治疗高危原发性肿瘤 c-erbB-2过表达与癌症的关系 高风险乳腺肿瘤是两个发展， 我们努力开发更好的乳腺癌癌基因相关标志物， 预后 c-erbB-2过表达（mRNA和p185erbB-2）的标准测定 蛋白质）和DNA扩增可能无法测量基本功能障碍 这种癌基因在某些乳腺癌中的作用。 与c-erbB-2不同， 雌激素和孕激素受体（ER，PR）水平表明 侵袭性肿瘤类型和更有利的患者预后。 像c-erbB-2， 然而，目前的受体测定不能测量受体功能， 以确定许多复发的患者， 不治之症 我们正在开发新的检测异常c-erbB-2的方法， ER功能将识别复发风险最高的原发性肿瘤。 同时，我们也在测量癌基因异常的发生率， 迄今为止研究较少的特定乳腺癌亚群：男性 乳腺肿瘤和非侵袭性原位癌。 c-erbB-2升高 扩增或过度表达解释了与 男性乳腺癌？ 原位癌中p185erbB-2过表达是由于 通过扩增c-erbB-2基因进行早期转化？ 检测 我们将测量与c-erbB-2功能相关的肿瘤水平， 转录反式激活因子，其介导c- erbB-2。 同时，我们将表征酪氨酸磷酸化蛋白质 p185erbB-2的底物，代表失调的信号转导 c-erbB-2以及其他各种酪氨酸蛋白的作用机制 激酶相关原癌基因和生长因子受体。 我们还将 检测抗p185erbB-2抗体和反义erbB-2寡聚体 在短期培养中生长的原代肿瘤细胞， 依赖于c-erbB-2表达失调的肿瘤， 恶性生长 受体异常的高危ER阳性肿瘤 功能将通过改变肿瘤细胞ER与 其基因特异性雌激素反应元件（ERE）。 最后，形成 这些ER-ERE复合物中的一种将与异常的肿瘤表达相关， ER依赖性应激反应蛋白srp-27的表达，以及 复发，以确定这些参数如何识别患者， 复发的风险更高。

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.