Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.
Integrin β5 contributes to the tumorigenic potential of breast cancer cells through the Src-FAK and MEK-ERK signaling pathways.
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DOI：
10.1038/onc.2012.320
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发表时间：
2013-06-20
期刊：
影响因子：
8
通讯作者：
Bakin, A. V.
中科院分区：
文献类型：
--
作者：
Bianchi-Smiraglia, A.;Paesante, S.;Bakin, A. V.
关键词：
肿瘤的进展、对治疗的反应和转移取决于肿瘤微环境。整合素是介导细胞与细胞外基质（ECM）相互作用的细胞粘附受体。αv-β-整合素家族参与肿瘤发生、治疗反应和癌症干细胞生物学。因此，了解特定整合素在癌症中的功能对于开发靶向整合素的治疗方法至关重要。本研究通过RNA干扰耗尽整合素β5和重新表达整合素β5来研究整合素β5在乳腺癌中的作用。在三阴性乳腺癌细胞中，整合素β5的缺失显著降低了肿瘤的生长和血管生成，而整合素β5的重新表达则挽救了这种表型。在整合素β5缺失的肿瘤中，肿瘤血管生成的减少与VEGF-A的低表达有关。缺乏整合素β5的肿瘤细胞迁移和增殖能力较低。生化分析表明，整合素β5介导Src-FAK和MEK-ERK信号通路独立运作，这些通路的抑制表现为整合素β5缺乏。乳腺癌细胞表达高水平的整合素β5，而整合素β3的表达仅限于间质室，而整合素β6在转移细胞中缺失。综上所述，这些发现表明整合素β5在乳腺癌细胞的致瘤潜能中起着至关重要的作用，并且整合素β5的靶向治疗对于目前大多数治疗方法难治性的三阴性乳腺癌尤其具有吸引力。
Cancer progression, response to therapy and metastasis depend on tumor microenvironment. Integrins are cell adhesion receptors that mediate interactions of cells with extracellular matrix (ECM). The αv-β-family of integrins contributes to tumorigenesis, response to therapy and cancer-stem cell biology. Thus, understanding the function of specific integrins in cancer is critical for development of therapeutic approaches targeting integrins. The study investigated the role of integrin β5 in breast carcinomas by depleting integrin β5 using RNA interference and re-expression of integrin β5. Depletion of integrin β5 in triple-negative breast carcinoma cells markedly reduced tumor take, growth, and tumor angiogenesis, while re-expression of integrin β5 rescued this phenotype. Reduction in tumor angiogenesis is associated with lower expression of VEGF-A in integrin β5-depleted tumors. Tumor cells deficient for integrin β5 have lower migration and proliferative capacities. Biochemical assays revealed that integrin β5 mediates Src-FAK and MEK-ERK signaling events that operate independently, and inhibition of these pathways phenocopies integrin β5-deficiency. Breast carcinoma cells express high levels of integrin β5, whereas expression of integrin β3 is limited to stromal compartments and integrin β6 is lost in metastatic cells. Together these findings show a critical role for integrin β5 in the tumorigenic potential of breast carcinoma cells and therapeutic targeting of integrin β5 is especially attractive for triple-negative breast carcinomas, which are refractory to most of the current therapies.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1186/bcr2572
发表时间：
2010
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Alvarez RH
通讯作者：
Alvarez RH
在两种血管生成途径中，差异alphav整联蛋白介导的RAS-ERK信号传导。
DOI：
10.1083/jcb.200304105
发表时间：
2003-09-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hood JD;Frausto R;Kiosses WB;Schwartz MA;Cheresh DA
通讯作者：
Cheresh DA
DOI：
10.1186/bcr2890
发表时间：
2011-06-27
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Colombo PE;Milanezi F;Weigelt B;Reis-Filho JS
通讯作者：
Reis-Filho JS
影响因子：
15.8
作者：
Lee TH;Seng S;Sekine M;Hinton C;Fu Y;Avraham HK;Avraham S
通讯作者：
Avraham S