NEW THARAPY FOR HER 2/NEU POSITIVE BREAST CANCER

HER-2/neu扩增或过表达发生在20-30 %的人类乳腺癌，与表达增加有关 患者预后不良。迫切需要新药来治疗 治疗这种疾病。多条证据表明，环氧合酶-2很重要 在致癌方面。COX-2缺乏对肠道和皮肤肿瘤的保护作用 在实验动物中形成。申请人发现， HER-2/neu阳性乳腺癌组织中COX-2表达升高。这引发了 选择性COX-2抑制剂预防Neu诱导的乳房的可能性 肿瘤的发生，就像最近在结肠癌和皮肤癌中显示的那样。这样做的一个目的是 因此，建议是确定药物抑制或 COX-2的基因消融抑制血管形成或抑制 MMTV/neu转基因小鼠乳腺肿瘤转移的研究也有越来越多的 临床前证据表明，核受体PPARγ的配体可能是 在预防或治疗乳腺癌方面有效。申请人已证明 PPARγ配体对HER-2/neu转化乳腺生长的抑制作用 抑制HER-2/neu介导的COX-2基因激活 表情。第二个目标将是确定曲格列酮是否为PPRP 伽马配体，防止MMTV/neu转基因小鼠乳腺肿瘤的发生 增强赫赛汀的抗肿瘤活性。最后，申请者将 阐明PPARγ配体引起G1期细胞周期停滞的机制 并抑制HER-2/neu介导的COX-2诱导。 研究将为做出合理的决定提供基础 女性应评估选择性COX-2抑制剂或PPARγ配体 HER-2/neu-高表达乳腺癌。

Amplification or overexpression of HER-2/neu occurs in 20-30 percent of human breast cancers, and increased expression has been associated with poor prognosis in the patients. New medications are urgently needed to treat this disease. Several lines of evidence suggest that COX-2 is important in carcinogenesis. COX-2 deficiency protects against intestinal and skin tumor formation in experimental animals. The applicant has discovered that levels of COX-2 are elevated in HER-2/neu-positive human breast cancer. This raises the possibility that selective COX-2 inhibitors will prevent neu-induced mammary tumorigenesis, as was recently shown for colon and skin cancer. One aim of this proposal, therefore, is to determine whether pharmacological inhibition or genetic ablation of COX-2 suppresses the formation of or inhibits the metastasis of mammary tumors in MMTV/neu transgenic mice. There is also growing preclinical evidence that ligands of the nuclear receptor PPAR gamma may be effective in preventing or treating breast cancer. The applicant has shown that PPAR gamma ligands inhibit the growth of HER-2/neu-transformed mammary epithelial cells and suppressed HER-2/neu-mediated activation of COX-2 gene expression. A second aim will be to determine whether troglitazone, a PPRP gamma ligand, prevents mammary tumorigenesis in MMTV/neu transgenic mice or enhances the antitumor activity of Herceptin. Finally, the applicant will elucidate the mechanisms by which PPAR gamma ligands cause G1 cell cycle arrest and inhibit HER-2/neu-mediated induction of COX- 2. The results of these studies will provide the basis for making a rational decision about whether selective COX-2 inhibitors or PPAR gamma ligands should be evaluated in women with HER-2/neu-overexpressing breast cancer.