CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers.
CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers.
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CD44同工型在乳腺癌中异质表达，并与肿瘤亚型和癌症干细胞标记相关。
DOI：
10.1186/1471-2407-11-418
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发表时间：
2011-09-29
期刊：
影响因子：
3.8
通讯作者：
Hegardt C
中科院分区：
文献类型：
--
作者：
Olsson E;Honeth G;Bendahl PO;Saal LH;Gruvberger-Saal S;Ringnér M;Vallon-Christersson J;Jönsson G;Holm K;Lövgren K;Fernö M;Grabau D;Borg A;Hegardt C
CD44细胞粘附分子在许多乳腺肿瘤中异常表达，并与转移过程以及假定的癌症干细胞（CSC）隔室有关。我们的目的是研究CD44的选择性剪接异构体与CSCs以及各种乳腺癌生物标志物和分子亚型之间的潜在关联。我们使用q-RT-PCR和外显子-外显子跨越法分析了187个乳腺肿瘤和13个细胞系中4种CD44选择性剪接亚型的表达以及CD44的总表达。免疫组化法检测TMA上ALDH1蛋白的表达。乳腺癌细胞系显示出CD44亚型的异质表达模式，当细胞作为乳腺球生长时，这种表达模式发生了很大的变化。通过免疫组织化学表征为CD44+/CD24-表型阳性的肿瘤与除CD44标准（CD44S）异构体外的所有异构体相关，CD44标准（CD44S）异构体缺乏所有变异外显子。相反，CSC标志物ALDH1强表达的肿瘤CD44S表达升高。CD44v2-v10亚型的高表达（保留所有变异外显子）与类固醇受体阳性状态、低增殖和腔A亚型相关。CD44v3-v10亚型也表现出类似的相关性，而CD44v3-v10的高表达与EGFR阳性、HER2阴性/低状态和基底样亚型相关。CD44S的高表达与强HER2染色和基底样肿瘤亚组相关。CD44异构体表达数据的无监督分层聚类分析将肿瘤分为四个主要聚类，这些聚类与分子亚型和10年总生存率的差异有显著相关性。我们证明了单个CD44亚型可以与不同的乳腺癌亚型和临床标志物（如HER2、ER和PgR）相关，这表明CD44剪接变体参与了特定的致癌信号通路。将CD44与CSCs和肿瘤进展联系起来的努力应该考虑各种CD44亚型的表达。
The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44+/CD24- phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs and tumor progression should consider the expression of various CD44 isoforms.
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影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
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影响因子：
7.4
作者：
Jumppanen, Mervi;Gruvberger-Saal, Sofia;Kauraniemi, Paivikki;Tanner, Minna;Bendahl, Par-Ola;Lundin, Mikael;Krogh, Morten;Kataja, Pasi;Borg, Ake;Ferno, Marten;Isola, Jorma
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影响因子：
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作者：
Dihge, Looket;Bendahl, Par-Ola;Ferno, Marten
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Ferno, Marten
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
11.5
作者：
Gruvberger-Saal, Sofia K.;Bendahl, Paer-Ola;Fernoe, Marten
通讯作者：
Fernoe, Marten