Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions
Chronic exposure to fulvestrant promotes overexpression of the c-Met receptor in breast cancer cells: implications for tumour-stroma interactions
复制标题
DOI：
10.1677/erc.1.01270
复制
发表时间：
2006-12-01
影响因子：
3.9
通讯作者：
Nicholson, Robert I.
中科院分区：
文献类型：
--
作者：
Hiscox, Stephen;Jordan, Nicola J.;Nicholson, Robert I.
我们以前的研究使用他莫昔芬耐药的细胞模型已经表明，内分泌不敏感状态的获得伴随着体外侵袭性表型。在这项研究中，我们希望确定这是否与部分雌激素受体激动剂有关，或者是否与较新的“纯”抗雌激素药物（以氟维司群为例）出现类似现象。我们的数据表明，在两个乳腺癌细胞系，MCF 7和T47 D的氟维司群耐药的发展，伴随着增强的迁移和侵袭表型在体外和HGF/SF受体，c-Met的过表达。重要的是，这些细胞中上调的c-Met表达促进了HGF/SF分泌基质成纤维细胞对它们的刺激，导致Src、Akt和ERK 1/2的激活，并显著增强了它们在体外的侵袭性表型。这些效应可能特别归因于c-Met受体的激活，因为包含c-Met的中和抗体或siRNA介导的c-Met表达敲低抑制了外源性HGF/SF、成纤维细胞条件培养基或与成纤维细胞共培养后刺激的侵袭和迁移。总之，这些体外数据表明，体内氟维司群耐药性的发展可能通过周围基质细胞增强细胞的迁移和侵袭行为而赋予细胞转移优势。
Our previous investigations using cell models of tamoxifen resistance have shown that the acquisition of an endocrine-insensitive state is accompanied by an invasive in vitro phenotype. In this study, we wished to determine whether this was specifically related to partial oestrogen receptor agonists or whether similar phenomena arise with the newer 'pure' anti-oestrogens, exemplified by fulvestrant. Our data demonstrate that the development of fulvestrant resistance in two breast cancer cell lines, MCF7 and T47D, is accompanied by an augmented migratory and invasive phenotype in vitro and overexpression of the HGF/SF receptor, c-Met. Importantly, upregulated c-Met expression in these cells facilitates their stimulation by HGF/SF-secreting stromal fibroblasts, leading to the activation of Src, Akt and ERK1/2 and a profound enhancement of their aggressive phenotype in vitro. These effects could be specifically attributable to activation of the c-Met receptor since the inclusion of neutralising antibodies to c-Met, or siRNA-mediated knockdown of c-Met expression, suppressed both invasion and migration stimulated by either exogenous HGF/SF, fibroblast-conditioned medium or following co-culture with fibroblast cells. Together, these in vitro data suggest that the development of fulvestrant resistance in vivo may confer a metastatic advantage to the cells by allowing their migratory and invasive behaviour to be augmented by surrounding stromal cells.