A Novel HOX Gene Target in Breast Cancer

描述(由申请人提供)： 乳腺癌是35岁至35岁的美国女性的主要死亡原因 现年55岁。我们已经克隆了一种名为BP1的新的人类同源框基因 是乳腺癌治疗的潜在靶点。来自15名患者的肿瘤 在新诊断的乳腺癌中，我们发现15例中有13例(87%)表达 BP1mRNA高表达，而其余的BP1mRNA检测不到 13%。相比之下，BP1在六个组织中只有一个表达(水平非常低) 正常的乳腺组织。BP1在高级别肿瘤中的表达为100%， 雌激素受体(ER)阴性、孕激素受体(PR)阴性的癌症， 但在ER阳性、PR阳性的乳腺癌中只有33%。有趣的是，BP1 研究还发现，乳腺癌细胞系中的mRNA水平也很高 被认为是致癌的。在此应用程序中，我们将测试以下假设 BP1是乳腺癌治疗的新靶点 肿瘤，并使用分子技术。目前，我们正在测量BP1 用RT-PCR方法检测乳腺肿瘤的组织学变化。在这一应用中，免疫组织化学分析 将被开发以便于分析BP1在组织学中的表达 横断面。与这笔拨款相关的是，之前对白血病的分子研究 提示BP1的表达正在转化，是肿瘤生存所必需的 白血病细胞系。如果BP1是抗凋亡途径的一部分，它的 在乳腺癌细胞中的表达可能也很重要。稳定的乳房 将建立过表达BP1的癌细胞株以确定是否 BP1的表达在体外正在转化。利用这些技术对基因阵列进行分析 细胞系将有助于识别可能是BP1和BP1靶点的基因 它所参与的路径。确定BP1水平下降是否 导致生长抑制或细胞凋亡，BP1的表达将在 利用遗传学和药理学方法建立乳腺癌细胞系。本研究 因此将结合临床和遗传方法来确定 BP1表达在乳腺癌中的重要性。

DESCRIPTION (provided by applicant): Breast cancer is the leading cause of death among American women who are 35 to 55 years of age. We have cloned a novel human homeobox gene called BP1 which is a potential target for therapy of breast cancer. In tumors from 15 patients with newly diagnosed breast cancer, we found that 13 of the 15 (87%) expressed high levels of BP1 mRNA, whereas BP1 mRNA was undetectable in the remaining 13%. In contrast, BP1 was expressed (at a very low level) in only one of six normal breast tissues. BP1 expression was seen in 100% of the high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative cancers, but in only 33% of ER positive, PR positive breast cancers. Interestingly, BP1 mRNA levels were also found to be high in breast cancer cell lines which are known to be tumorigenic. In this application, we will test the hypothesis that BP1 is a new therapeutic target in breast cancer by analyzing additional tumors and using molecular techniques. Currently we are measuring BP1 in breast tumors by RT-PCR. In this application, immunohistochemical analysis will be developed to facilitate analysis of BP1 expression in histological sections. Of relevance to this grant, previous molecular studies in leukemia suggest that BP1 expression is transforming and is required for survival of a leukemia cell line. If BP1 is part of an anti-apoptotic pathway, its expression may be important in breast cancer cells as well. Stable breast cancer cell lines overexpressing BP1 will be established to determine whether BP1 expression is transforming in vitro. Analysis of a gene array using these cell lines will help to identify genes which may be targets of BP1 and pathways in which it is involved. To determine whether decreasing BP1 levels leads to growth inhibition or apoptosis, BP1 expression will be reduced in breast cancer cell lines using genetic and pharmacological methods. This study will therefore combine clinical and genetic approaches to determine the importance of BP1 expression in breast cancer.