Identification and functional analysis of novel oncogenes involved in the breast cancer genesis and promotion

叉头转录因子FoxA1被认为与乳腺肿瘤发生有关。然而，FoxA1在乳腺癌发展中的确切作用是有争议的。我们检测了FoxA1在35个人乳腺癌细胞系中的表达，并将其与乳腺癌预后不良的标志物ErbB2进行了比较。我们发现FoxA1在所有ErbB2阳性细胞系和ErbB2阴性细胞系的一个子集中以高水平表达。通过RNA干扰下调FoxA1显著抑制ErbB2阴性和FoxA1阳性乳腺癌细胞系的增殖。下调FoxA1也通过诱导细胞凋亡增强赫赛汀对ErbB2阳性细胞系的毒性作用。综上所述，我们的研究结果表明FoxA1作为一种谱系特异性癌基因在乳腺癌细胞的增殖中起重要作用，近20%的乳腺癌细胞表现出组成性NF-κ B B活性，其诱导与肿瘤生长、转移和血管生成有关的多个基因的表达，但其组成性激活的机制尚不清楚。为了回答这个问题，我们首先用电泳迁移率变动分析法评估了125个来自不同组织的人癌细胞系的基础NF-B活性。我们正在使用显示高NF-κ B活性的细胞系分析其机制。

The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer. We found that FoxA1 is expressed at high levels in all ErbB2-positive cell lines and a subset of ErbB2-negative cell lines. Down-regulation of FoxA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FoxA1-positive breast cancer cell lines. Down-regulation of FoxA1 also enhanced the toxic effect of Herceptin on ErbB2-positive cell lines through induction of apoptosis. Taken together, our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells.Almost 20% of cancer cells show constitutive NF-кB activity, which induce expression of several genes involved in tumor growth, metastasis and angiogenesis, however, the mechanism of the constitutive activation is unclear. To answer this question, we first evaluated basal NF-кB activities of 125 human cancer cell lines from various tissues with electorophoretic mobility shift assays. We are analyzing the mechanism using the cell lines showing high NF-кB activity.