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

需要用特殊形式的佐剂治疗高危原发肿瘤 C-erbB-2过度表达与治疗及公认的相关性 高危乳腺肿瘤的两个进展重新引起了人们的关注 我们为开发更好的乳腺癌癌基因相关标志物所做的努力 预后。C-erbB-2过表达的标准检测(mRNA和p185erbB-2 蛋白质)和DNA扩增可能不能衡量根本的功能障碍 这种癌基因在一些乳腺癌中的作用。与c-erbB-2不同，肿瘤增加 雌激素和孕激素受体(ER、PR)水平表示 侵袭性肿瘤类型和更有利的患者预后。就像c-erbB-2一样， 然而，目前的受体分析不能测量受体的功能，因此失败了。 以确定许多激素反应迟钝和复发的患者 不治之症。我们正在开发新的c-erb B-2异常检测方法 ER功能，将识别复发风险最高的原发肿瘤。 同时，我们正在测量癌基因异常的发生率 迄今研究甚少的特定乳腺癌亚群：男性 乳腺肿瘤和非侵袭性原位癌。C-erb B-2的增加 扩增或过度表达可解释低存活率与 男性乳腺癌？P185erbB-2在原位癌中的过度表达 C-erbB-2基因扩增的早期转化？要检测 与c-erbB-2功能相关的异常我们将测量肿瘤水平 一种转录反式激活因子(S)，介导c-蛋白的过度表达 ErbB-2。此外，我们还将对酪氨酸磷酸化蛋白进行表征 代表失调信号转导的p185erbB-2底物 C-erbB-2和其他各种酪氨酸蛋白的作用机制 激酶相关的原癌基因和生长因子受体。我们还将 检测抗p185-erb B-2抗体和反义-erb B-2寡聚体 在短期培养中生长的原代肿瘤细胞以鉴定个体 依赖c-erbB-2异常表达的肿瘤 恶性生长。受体异常的高危ER阳性肿瘤 将通过改变肿瘤细胞ER与其体外结合来鉴定其功能 其基因特异性雌激素反应元件(ERE)。最后，阵型 其中ER-ERE复合体与肿瘤的异常表达相关 内质网依赖的应激反应蛋白SRP-27和临床死亡率 复发以确定这些参数在多大程度上识别患者 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.