BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases.
BMI1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases.
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DOI：
10.1038/onc.2009.165
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发表时间：
2009-08-27
期刊：
影响因子：
8
通讯作者：
Green, J. E.
中科院分区：
文献类型：
--
作者：
Hoenerhoff, M. J.;Chu, I.;Barkan, D.;Liu, Z-y;Datta, S.;Dimri, G. P.;Green, J. E.
BMI 1是多梳转录抑制子组的成员，其通过抑制INK 4A/ARF肿瘤抑制基因座在干细胞维持和肿瘤发生中起作用。BMI 1的过表达与包括乳腺癌在内的几种人类癌症的不良预后相关。我们以前已经表明，BMI 1与H-RAS合作，通过不依赖于INK 4A/ARF基因座的多种生长途径的失调诱导MCF 10A人乳腺上皮细胞的转化。在这项研究中，我们证明，BMI 1与H-RAS合作，以促进体外增殖，侵袭和抗凋亡，并增加乳腺脂肪垫异种移植物的自发转移率，包括新的脑转移。此外，与H-RAS合作，BMI 1通过加速细胞增殖和抑制细胞凋亡，使用血源性扩散的尾静脉模型诱导肺中的暴发性转移性疾病。最后，我们表明，在几个已建立的乳腺癌细胞系中，BMI 1的敲低导致体外和体内致癌行为降低。综上所述，BMI 1与H-RAS协同诱导具有侵袭性和转移性的表型，并伴有罕见的脑转移发生，使其成为诊断和治疗侵袭性乳腺癌的重要靶点。
BMI1 is a member of the polycomb group of transcription repressors that functions in stem cell maintenance and oncogenesis through inhibition of the INK4A/ARF tumour suppressor locus. Overexpression of BMI1 is associated with poor prognosis in several human cancers, including breast cancer. We have previously shown that BMI1 collaborates with H-RAS to induce transformation of MCF10A human mammary epithelial cells via dysregulation of multiple growth pathways independent of the INK4A/ARF locus. In this study, we demonstrate that BMI1 collaborates with H-RAS to promote increased proliferation, invasion, and resistance to apoptosis in vitro, and an increased rate of spontaneous metastases from mammary fat pad xenografts including novel metastases to the brain. Furthermore, in collaboration with H-RAS, BMI1 induced fulminant metastatic disease in the lung using a tail vein model of haematogenous spread through accelerated cellular proliferation and inhibition of apoptosis. Finally, we show that knockdown of BMI1 in several established breast cancer cell lines leads to decreased oncogenic behaviour in vitro and in vivo. In summary, BMI1 collaborates with H-RAS to induce an aggressive and metastatic phenotype with the unusual occurrence of brain metastasis, making it an important target for diagnosis and treatment of aggressive breast cancer.
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影响因子：
11.2
作者：
Datta, Sonal;Hoenerhoff, Mark J.;Dimri, Goberdhan P.
通讯作者：
Dimri, Goberdhan P.
影响因子：
5.3
作者：
Desprez, PY;Lin, CQ;Campisi, J
通讯作者：
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影响因子：
8.8
作者：
通讯作者：
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影响因子：
4.3
作者：
Glinsky, GV
通讯作者：
Glinsky, GV
影响因子：
6.2
作者：
Bendell, JC;Domchek, SM;Winer, E
通讯作者：
Winer, E