Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer.
Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer.
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DOI：
10.1158/0008-5472.can-07-6316
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Sweeney, Colleen
中科院分区：
文献类型：
--
作者：
Miller, Jamie K.;Shattuck, David L.;Ingalla, Ellen Q.;Yen, Lily;Borowsky, Alexander D.;Young, Lawrence J. T.;Cardiff, Robert D.;Carraway, Kermit L., III;Sweeney, Colleen
ErbB 2受体酪氨酸激酶在约25%的乳腺肿瘤中过表达，导致患者预后不良和治疗耐药性。在这里，我们研究了最近发现的ErbB负调控因子LRIG 1在ErbB 2（+）乳腺癌中的作用。我们观察到LRIG 1蛋白水平在ErbB 2诱导的转基因小鼠乳腺肿瘤以及大多数ErbB 2（+）人类乳腺肿瘤中受到显著抑制。这些观察结果提出了LRIG 1缺失可能有助于ErbB 2（+）乳腺肿瘤的发生或生长的可能性。在ErbB 2过表达的乳腺肿瘤细胞系MDA-MB-453和BT474中，RNAi介导的内源性LRIG 1敲低进一步提高了这些细胞中的ErbB 2并增强了细胞增殖。相反，LRIG 1的异位表达逆转了这些趋势。有趣的是，我们观察到LRIG 1蛋白水平在乳腺肿瘤细胞中响应ErbB受体活化而被抑制，但在永生化的非转化乳腺上皮细胞中不受ErbB活化的影响。我们的观察表明，LRIG 1蛋白水平的抑制是乳腺肿瘤的一个共同特征。此外，我们的观察指出，在乳腺肿瘤细胞中存在前馈调节环，其中异常的ErbB 2信号传导抑制LRIG 1蛋白水平，这反过来又有助于ErbB 2过表达。
The ErbB2 receptor tyrosine kinase is overexpressed in ~ 25% of breast tumors and contributes to poor patient prognosis and therapeutic resistance. Here we examine the role of the recently discovered ErbB negative regulator LRIG1 in ErbB2 (+) breast cancer. We observe that LRIG1 protein levels are significantly suppressed in ErbB2-induced mammary tumors in transgenic mice as well as the majority of ErbB2 (+) human breast tumors. These observations raise the possibility that LRIG1 loss could contribute to the initiation or growth of ErbB2 (+) breast tumors. RNAi-mediated knockdown of endogenous LRIG1 in the ErbB2 overexpressing breast tumor cell lines MDA-MB-453 and BT474 further elevates ErbB2 in these cells and augments cellular proliferation. In contrast, ectopic expression of LRIG1 reverses these trends. Interestingly, we observe that LRIG1 protein levels are suppressed in response to ErbB receptor activation in breast tumor cells, but are unaffected by ErbB activation in immortalized non-transformed breast epithelial cells. Our observations indicate that the suppression of LRIG1 protein levels is a common feature of breast tumors. Moreover, our observations point to the existence of a feed-forward regulatory loop in breast tumor cells where aberrant ErbB2 signaling suppresses LRIG1 protein levels, which in turn contributes to ErbB2 overexpression.