Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer.
Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer.
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DOI：
10.1158/0008-5472.can-09-0042
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发表时间：
2009-05-15
期刊：
影响因子：
11.2
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Miller TW;Pérez-Torres M;Narasanna A;Guix M;Stål O;Pérez-Tenorio G;Gonzalez-Angulo AM;Hennessy BT;Mills GB;Kennedy JP;Lindsley CW;Arteaga CL
在三种雌激素受体（ER）阳性乳腺癌细胞系中用shRNA敲低肿瘤抑制磷酸酶PTEN导致PI 3 K和AKT活性增加，对他莫昔芬和氟维司群耐药，以及非依赖性生长。在MCF-7细胞中，PTEN基因敲低可诱导ER转录活性上调，而在T47 D和MDA-361细胞中，则可诱导ER蛋白水平和转录活性降低。他莫昔芬和氟维司群处理抑制了所有shPTEN细胞系中雌二醇诱导的ER转录活性，但并未消除PTEN敲低诱导的细胞增殖增加。PTEN敲除增加了IGF-I和ErbB 3受体酪氨酸激酶的基础和配体诱导的激活，并延长了p85 PI 3 K亚基与IGF-IR效应子IRS-1和ErbB 3的结合，暗示了PTEN在PI 3 K上游信号转导的调节中。与这些数据一致，在原发性乳腺癌的组织裂解物阵列中，PTEN水平与酪氨酸磷酸化IGF-IR水平负相关。用酪氨酸激酶抑制剂抑制IGF-IR和/或ErbB 2介导的ErbB 3激活恢复了他莫昔芬和氟维司群对shPTEN细胞的生长抑制作用和细胞依赖性，表明共靶向ER和受体酪氨酸激酶途径有望治疗ER+、PTEN缺陷型乳腺癌患者。
Knockdown of the tumor suppressor phosphatase PTEN with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased PI3K and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the upregulation of ER transcriptional activity in MCF-7 cells, but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced ER transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the IGF-I and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-IR effector IRS-1 and with ErbB3, implicating PTEN in the modulation of signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone-dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells, suggesting that co-targeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.