HER-2/NEU ALTERATIONS IN BREAST AND OVARIAN CANCER

人类乳腺癌和卵巢癌共占162，000例新病例， 每年有大约三分之一的癌症发生在女性身上。 此外，它们每年造成55 000人死亡， 四分之一的女性癌症相关死亡。 HER-2/neu原癌基因 一种假定的生长因子受体，与 表皮生长因子受体。 我们实验室的研究表明， 显示该基因在约30%的人类中扩增和/或过表达， 乳腺癌和卵巢癌。 此外，这种变化与 发生肿瘤的患者的临床结果较差。 的 本建议的目的是调查这一可能的作用， 改变在这些疾病的发病机制中起作用。 转染 将研究将人类乳腺和卵巢细胞从细胞转化为 HER-2/neu基因的单拷贝和低水平表达， 具有模拟发现的改变的扩增/过表达基因的细胞 在人类乳腺癌和卵巢癌中。 这种生物效应 将研究改变，包括对DNA合成，细胞 生长、细胞侵袭性和裸鼠中的致瘤性。 在 此外，针对该基因产物的细胞外结构域的抗体将被 用于含有这种改变的细胞的体外和体内研究， 确定抗体是否改变了由其介导的生物效应， 变更。 这些研究可能会导致新的治疗方法的开发 基于这种癌基因改变来治疗这些疾病。

Human breast and ovarian cancer together account for 162,000 new cases of cancer per year or essentially one third of all cancers occurring in women. In addition, they account for 55,000 deaths per year, or essentially one quarter of cancer related deaths in women. The HER-2/neu proto-oncogene is a putative growth factor receptor which is related to, but distinct from the epidermal growth factor receptor. Studies done in our laboratory have shown that this gene is amplified and/or overexpressed in ~30% of human breast and ovarian cancers. Moreover, this alteration is associated with a poor clinical outcome for patients in whose tumors it occurs. The objective of this proposal is to investigate the possible role this alteration plays in the pathogenesis of these diseases. Transfection studies will be done to convert human breast and ovarian cells from cells with a single copy and low levels of expression of the HER-2/neu gene to cells with an amplified/overexpressed gene mimicking the alteration found in human breast and ovarian cancer. The biologic effects of this alteration will be investigated, including effects on DNA synthesis, cell growth, cell invasiveness, and tumorigenicity in the nude mouse. In addition, antibodies to extracellular domains of this gene product will be used in vitro and in vivo studies of cells containing this alteration to determine if the antibodies change the biologic effects mediated by this alteration. These studies may lead to development of novel therapeutic approaches to these diseases based on this oncogene alteration.