FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer.
FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer.
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DOI：
10.3892/ijo_00000313
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发表时间：
2009-07
影响因子：
5.2
通讯作者：
Lam EW
中科院分区：
文献类型：
--
作者：
Francis RE;Myatt SS;Krol J;Hartman J;Peck B;McGovern UB;Wang J;Guest SK;Filipovic A;Gojis O;Palmieri C;Peston D;Shousha S;Yu Q;Sicinski P;Coombes RC;Lam EW
酪氨酸激酶受体HER 2是乳腺癌的重要预后标志物和治疗靶点;然而，HER 2的下游靶点和生物效应器仍不清楚。我们研究了乳腺癌中HER 2和转录因子FoxM 1之间的关系。在乳腺癌细胞系、石蜡包埋的乳腺癌患者样品中以及在纯化的乳腺上皮细胞中的mRNA水平上比较HER 2和FoxM 1表达水平。为了进一步研究HER 2和FoxM 1表达之间的关系，我们在乳腺癌细胞系中过度表达或siRNA介导的内源性HER 2缺失。此外，还使用乳腺上皮靶向HER 2（neu）转基因小鼠模型评估HER 2对FoxM 1水平的影响。此外，研究了HER 2-酪氨酸激酶抑制剂拉帕替尼对HER 2阳性乳腺癌细胞中FoxM 1的影响。在乳腺癌细胞系和石蜡包埋的乳腺癌患者样本中，HER 2蛋白水平与FoxM 1表达直接相关。此外，在纯化的乳腺上皮细胞中，HER 2的过表达与高水平的FoxM 1 mRNA相关，这表明FoxM 1表达的上调至少部分是转录介导的。此外，内源性HER 2的过表达或消除导致FoxM 1表达的平行变化。重要的是，乳腺上皮靶向HER 2小鼠肿瘤也导致FoxM 1表达增加，表明HER 2介导的FoxM 1表达发生在体内，可能是HER 2靶向治疗的关键下游效应子。事实上，用拉帕替尼治疗乳腺癌细胞在蛋白质、mRNA和基因启动子水平上降低了FoxM 1的表达。此外，对正常和乳腺癌患者样本的分析显示，FoxM 1在蛋白质和mRNA水平的表达升高与乳腺癌的发展相关，但与癌症进展和生存率无关。我们的研究结果表明，HER 2受体调节FoxM 1转录因子的表达，这在乳腺癌的发展中有一定的作用。
The tyrosine kinase receptor, HER2 is a crucial prognostic marker and therapeutic target for breast cancer; however, the downstream targets and biological effectors of HER2 remain unclear. We investigated the relationship between HER2 and the transcription factor FoxM1 in breast cancer. HER2 and FoxM1 expression levels were compared in breast carcinoma cell lines, paraffin embedded breast cancer patient samples and at the mRNA level in purified breast epithelial cells. To further examine the relationship between HER2 and FoxM1 expression, we either overexpressed or siRNA-mediated depleted endogenous HER2 in breast cancer cell lines. Additionally, a mammary epithelium-targeted HER2 (neu) transgenic mouse model was also used to assess the effect of HER2 on FoxM1 levels. Furthermore, the effect of the HER2-tyrosine kinase inhibitor lapatinib on FoxM1 in HER2 positive breast cancer cells was investigated. HER2 protein levels directly correlated with FoxM1 expression in both breast carcinoma cell lines and paraffin embedded breast cancer patient samples. Moreover, in purified breast epithelial cells, overexpression of HER2 was associated with high levels of FoxM1 mRNA, suggesting that the upregulation of FoxM1 expression is at least partially mediated transcriptionally. Furthermore, overexpression or ablation of endogenous HER2 resulted in parallel changes in FoxM1 expression. Critically, mammary epithelium-targeted HER2 mouse tumours also resulted in increased FoxM1 expression, suggesting that HER2 directed FoxM1 expression occurs in vivo and may be a critical downstream effector of HER2-targeting therapies. Indeed, treatment of breast cancer cells with lapatinib reduced FoxM1 expression at protein, mRNA and gene promoter levels. Moreover, analysis of normal and breast cancer patient samples revealed that elevated FoxM1 expression at protein and mRNA levels correlated with breast cancer development, but not significantly with cancer progression and survival. Our results indicate that the HER2 receptor regulates the expression of the FoxM1 transcription factor, which has a role in breast cancer development.
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Clevers, H
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