Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan.
Overexpression of CD44 accompanies acquired tamoxifen resistance in MCF7 cells and augments their sensitivity to the stromal factors, heregulin and hyaluronan.
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DOI：
10.1186/1471-2407-12-458
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发表时间：
2012-10-06
期刊：
影响因子：
3.8
通讯作者：
Gee J
中科院分区：
文献类型：
--
作者：
Hiscox S;Baruha B;Smith C;Bellerby R;Goddard L;Jordan N;Poghosyan Z;Nicholson RI;Barrett-Lee P;Gee J
乳腺癌对内分泌治疗的获得性耐药是一个重要的问题，复发与局部和/或区域复发和频繁的远处转移有关。乳腺癌细胞模型显示，内分泌抵抗伴随着攻击性行为的增加，部分原因是生长因子受体信号传导的改变，特别是与erbB家族受体有关。最近，我们发现CD44，一种已知与生长因子受体相互作用的跨膜细胞粘附受体，在他莫昔芬耐药（TamR） MCF7乳腺癌细胞中表达上调。本研究的目的是探讨CD44上调在MCF7细胞获得性他莫昔芬耐药模型中的后果，特别是CD44可能影响erbB活性以促进不良表型的假设。采用RT-PCR、Western blotting和免疫细胞化学检测CD44在MCF7和TamR细胞中的表达。免疫荧光和免疫沉淀研究显示CD44-erbB相关。用CD44配体、透明质子（HA）或heregulin处理TamR细胞（±sirna介导的CD44抑制）或MCF7细胞（±转染CD44基因），并测定其体外生长（MTT）、迁移（Boyden chamber和伤口愈合）和侵袭（Matrigel transwell迁移）。使用Western blotting评估erbB信号传导。在CD44 siRNA存在或不存在的情况下，通过免疫沉淀确定HA对TamR细胞中erbB家族二聚化的影响。TamR细胞过度表达CD44，并在细胞表面与erbB2结合。sirna介导的TamR细胞CD44抑制显著减弱其对heregulin的应答，抑制heregulin诱导的细胞迁移和侵袭。此外，TamR细胞表现出对HA的敏感性增强，HA处理导致erbB二聚化的调节，erbB2和EGFR的配体非依赖性激活以及诱导细胞迁移。缺乏内源性CD44的MCF7细胞中，CD44的过表达产生ha敏感表型，ha刺激促进erbB/EGFR的激活和迁移。这些数据表明，CD44在他莫昔芬耐药的背景下发挥了重要作用，它可能增强细胞对erbB配体和HA的反应，这些因素据报道存在于体内肿瘤微环境中。因此，在内分泌抵抗的情况下，CD44可能是乳腺癌进展的重要决定因素。
Acquired resistance to endocrine therapy in breast cancer is a significant problem with relapse being associated with local and/or regional recurrence and frequent distant metastases. Breast cancer cell models reveal that endocrine resistance is accompanied by a gain in aggressive behaviour driven in part through altered growth factor receptor signalling, particularly involving erbB family receptors. Recently we identified that CD44, a transmembrane cell adhesion receptor known to interact with growth factor receptors, is upregulated in tamoxifen-resistant (TamR) MCF7 breast cancer cells. The purpose of this study was to explore the consequences of CD44 upregulation in an MCF7 cell model of acquired tamoxifen resistance, specifically with respect to the hypothesis that CD44 may influence erbB activity to promote an adverse phenotype. CD44 expression in MCF7 and TamR cells was assessed by RT-PCR, Western blotting and immunocytochemistry. Immunofluorescence and immunoprecipitation studies revealed CD44-erbB associations. TamR cells (± siRNA-mediated CD44 suppression) or MCF7 cells (± transfection with the CD44 gene) were treated with the CD44 ligand, hyaluronon (HA), or heregulin and their in vitro growth (MTT), migration (Boyden chamber and wound healing) and invasion (Matrigel transwell migration) determined. erbB signalling was assessed using Western blotting. The effect of HA on erbB family dimerisation in TamR cells was determined by immunoprecipitation in the presence or absence of CD44 siRNA. TamR cells overexpressed CD44 where it was seen to associate with erbB2 at the cell surface. siRNA-mediated suppression of CD44 in TamR cells significantly attenuated their response to heregulin, inhibiting heregulin-induced cell migration and invasion. Furthermore, TamR cells exhibited enhanced sensitivity to HA, with HA treatment resulting in modulation of erbB dimerisation, ligand-independent activation of erbB2 and EGFR and induction of cell migration. Overexpression of CD44 in MCF7 cells, which lack endogenous CD44, generated an HA-sensitive phenotype, with HA-stimulation promoting erbB/EGFR activation and migration. These data suggest an important role for CD44 in the context of tamoxifen-resistance where it may augment cellular response to erbB ligands and HA, factors that are reported to be present within the tumour microenvironment in vivo. Thus CD44 may present an important determinant of breast cancer progression in the setting of endocrine resistance.
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影响因子：
4.8
作者：
Bourguignon, Lilly Y. W.;Gilad, Eli;Peyrollier, Karine
通讯作者：
Peyrollier, Karine
影响因子：
3.9
作者：
Hiscox, Stephen;Jordan, Nicola J.;Nicholson, Robert I.
通讯作者：
Nicholson, Robert I.
影响因子：
3.9
作者：
Hiscox, Stephen;Morgan, L.;Nicholson, Robert I.
通讯作者：
Nicholson, Robert I.
影响因子：
168.9
作者：
Davies, C.;Godwin, J.;Gray, R.;Clarke, M.;Darby, S.;McGale, P.;Wang, Y. C.;Peto, R.;Pan, H. C.;Cutter, D.;Taylor, C.;Ingle, J.
通讯作者：
Ingle, J.
影响因子：
15.9
作者：
Brown, Rhonda L.;Reinke, Lauren M.;Cheng, Chonghui
通讯作者：
Cheng, Chonghui