The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer.
The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer.
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DOI：
10.1186/s12885-018-4500-9
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发表时间：
2018-05-23
期刊：
影响因子：
3.8
通讯作者：
Bianchi F
中科院分区：
文献类型：
--
作者：
Forte L;Turdo F;Ghirelli C;Aiello P;Casalini P;Iorio MV;D'Ippolito E;Gasparini P;Agresti R;Belmonte B;Sozzi G;Sfondrini L;Tagliabue E;Campiglio M;Bianchi F
CDCP 1是一种具有肿瘤促转移活性的跨膜蛋白，最近被鉴定为TNBC的预后标志物，TNBC是最具侵袭性的乳腺癌亚型，仍然缺乏有效的分子靶向治疗。驱动CDCP 1过度表达的机制尚未完全了解，尽管来自肿瘤微环境的几种刺激，如伤口愈合液（WHF）中存在的因子，据报道会增加CDCP 1水平。用PDGF-BB刺激MDA-MB-231细胞后，通过Western blot检测CDCP 1、PDGFRβ和ERK 1/2细胞的表达，类似地，在一组TNBC细胞系中，在存在或不存在ERK 1/2抑制剂的情况下，检测CDCP 1、PDGFRβ和ERK 1/2细胞的表达。在MDA-MB-231细胞中建立PDGFRβ的敲低，以检测WHF处理后的CDCP 1。采用免疫组化法检测TNBC临床标本中CDCP 1和PDGFRβ的表达。我们发现PDGF-BB介导的PDGFRβ激活通过下游ERK 1/2的激活增加CDCP 1蛋白表达。ERK 1/2活性的抑制本身减少CDCP 1表达，证据加强其在CDCP 1表达调节中的作用。TNBC细胞中PDGFRβ的敲低损害了WHF处理诱导的CDCP 1增加，突出了该受体作为WHF介导的CDCP 1诱导的中心参与者的作用。在TNBC标本中观察到CDCP 1和PDGFRβ免疫组织化学染色之间的显著相关性，与CDCP 1基因获得无关，因此证实了PDGF-BB/PDGFRβ轴在CDCP 1表达调节中的相关性。我们已经确定PDGF-BB/PDGFRβ介导的通路是通过ERK 1/2活化调节TNCB中CDCP 1的新参与者。我们的研究结果为PDGFRβ和ERK 1/2抑制剂在靶向CDCP 1阳性TNBC侵袭性特征方面的潜在用途提供了基础。本文的在线版本（10.1186/s12885-018-4500-9）包含补充材料，可供授权用户使用。
CDCP1, a transmembrane protein with tumor pro-metastatic activity, was recently identified as a prognostic marker in TNBC, the most aggressive breast cancer subtype still lacking an effective molecular targeted therapy. The mechanisms driving CDCP1 over-expression are not fully understood, although several stimuli derived from tumor microenvironment, such as factors present in Wound Healing Fluids (WHFs), reportedly increase CDCP1 levels. The expression of CDCP1, PDGFRβ and ERK1/2cell was tested by Western blot after stimulation of MDA-MB-231 cells with PDGF-BB and, similarly, in presence or not of ERK1/2 inhibitor in a panel of TNBC cell lines. Knock-down of PDGFRβ was established in MDA-MB-231 cells to detect CDCP1 upon WHF treatment. Immunohistochemical staining was used to detect the expression of CDCP1 and PDGFRβ in TNBC clinical samples. We discovered that PDGF-BB-mediated activation of PDGFRβ increases CDCP1 protein expression through the downstream activation of ERK1/2. Inhibition of ERK1/2 activity reduced per se CDCP1 expression, evidence strengthening its role in CDCP1 expression regulation. Knock-down of PDGFRβ in TNBC cells impaired CDCP1 increase induced by WHF treatment, highlighting the role if this receptor as a central player of the WHF-mediated CDCP1 induction. A significant association between CDCP1 and PDGFRβ immunohistochemical staining was observed in TNBC specimens, independently of CDCP1 gene gain, thus corroborating the relevance of the PDGF-BB/PDGFRβ axis in the modulation of CDCP1 expression. We have identified PDGF-BB/PDGFRβ–mediated pathway as a novel player in the regulation of CDCP1 in TNCBs through ERK1/2 activation. Our results provide the basis for the potential use of PDGFRβ and ERK1/2 inhibitors in targeting the aggressive features of CDCP1-positive TNBCs. The online version of this article (10.1186/s12885-018-4500-9) contains supplementary material, which is available to authorized users.
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影响因子：
8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1011777108
发表时间：
2011-02-01
影响因子：
11.1
作者：
Razorenova, Olga V.;Finger, Elizabeth C.;Giaccia, Amato J.
通讯作者：
Giaccia, Amato J.
影响因子：
8
作者：
Benes, C. H.;Poulogiannis, G.;Cantley, L. C.;Soltoff, S. P.
通讯作者：
Soltoff, S. P.
影响因子：
11.2
作者：
D'Ippolito, Elvira;Plantamura, Ilaria;Iorio, Marilena V.
通讯作者：
Iorio, Marilena V.
影响因子：
8
作者：
Bhatt, AS;Erdjument-Bromage, H;Moasser, MM
通讯作者：
Moasser, MM