HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.
HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.
复制标题
DOI：
10.1038/onc.2015.489
复制
发表时间：
2016-08-11
期刊：
影响因子：
8
通讯作者：
Gudjonsson T
中科院分区：
文献类型：
--
作者：
Ingthorsson S;Andersen K;Hilmarsdottir B;Maelandsmo GM;Magnusson MK;Gudjonsson T
表皮生长因子受体(EGFR)激酶家族的成员在乳腺形态发生和癌症中起重要作用。EGFR2/HER2和EGFR的表达在某些乳腺癌亚型中具有预后价值，如HER2扩增、基底细胞样癌和腔型B型乳腺癌。许多临床批准的小分子抑制物和单抗被设计用于靶向HER2和/或EGFR。然而，关于这两种受体如何在正常乳腺上皮中表达，它们对细胞分化有什么影响，以及它们如何参与肿瘤转化，人们仍然知之甚少。D492是一种具有干细胞特性的乳腺上皮细胞系，可在三维(3D)培养中经历上皮向间充质转化(EMT)，生成腔上皮细胞和肌上皮细胞，并形成复杂的分支结构。在这里，我们证明了HER2在D492(D492HER2)中的过表达导致了EMT，失去了接触生长抑制，并在体内增加了致癌潜力。此外，HER2过表达还抑制了内源性EGFR的表达。在D492HER2(D492HER2/EGFR)中重新引入EGFR部分逆转了细胞的间质状态，因为在3D培养和体内都重新出现了上皮表型。D492HER2/EGFR异种移植瘤生长速度慢于D492HER2肿瘤，而单独表达EGFR(D492EGFR)在体内不是致癌的。与EGFR介导的上皮表型一致，在3D培养中，EGFR的过表达推动细胞向肌上皮表型转变。两种临床批准的抗HER2和EGFR疗法，曲妥珠单抗和西妥昔单抗，在D492HER2异种移植瘤上单独和联合进行了效果测试。曲妥珠单抗与未经处理的对照相比有生长抑制作用，而西妥昔单抗的作用有限。当联合用药时，曲妥珠单抗的生长抑制作用不那么明显。总而言之，我们的数据表明，在HER2过表达的D492细胞中，EGFR可以通过推动细胞向上皮分化而发挥肿瘤抑制因子的作用。
The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492HER2) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492HER2 (D492HER2/EGFR) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492HER2/EGFR xenografts grow slower than the D492HER2 tumors, while overexpression of EGFR alone (D492EGFR) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492HER2 xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.