Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance.
Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance.
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DOI：
10.1158/0008-5472.can-11-2192
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发表时间：
2011-12-15
期刊：
影响因子：
11.2
通讯作者：
Kitsis RN
中科院分区：
文献类型：
--
作者：
Medina-Ramirez CM;Goswami S;Smirnova T;Bamira D;Benson B;Ferrick N;Segall J;Pollard JW;Kitsis RN
ARC（具有半胱天冬酶募集结构域的凋亡抑制因子）抑制死亡受体和线粒体/ER介导的凋亡途径。虽然主要在终末分化细胞中表达，但ARC在各种人类癌症中显著上调，其潜在贡献尚未确定。在这项研究中，我们提供的证据，多个关键的病理生理功能的ARC在乳腺癌的发生。在乳腺癌的多瘤中T抗原（PyMT）转基因小鼠模型中，其中内源性ARC强烈上调，ARC编码基因nol 3的缺失降低了原发性肿瘤负荷，而不影响肿瘤发作或多重性。更值得注意的是，ARC缺陷还限制了肿瘤细胞的侵袭和循环癌细胞的数量，显著减少了肺转移的数量。相反，ARC在PyMT衍生的转移性乳腺癌细胞系中的异位过表达增加了体外侵袭和体内肺转移。我们在基于MDA-MB-231衍生的LM 2转移性乳腺癌细胞的人源化原位模型中证实了这些结果，其中证明了RNAi介导的ARC水平敲低可减少肿瘤体积、局部侵袭和肺转移。最后，我们发现内源性ARC水平在原发性肿瘤以及入侵细胞群体中赋予化学抗性。我们的研究结果表明，ARC通过驱动原发性肿瘤生长、侵袭和转移以及促进侵袭细胞的化疗耐药性来促进乳腺癌的发生。
ARC (Apoptosis Repressor with Caspase recruitment domain) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. While expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiological functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, where endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was demonstrated to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors as well as invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion and metastasis as well as by promoting chemoresistance in invasive cells.