HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab.
HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab.
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DOI：
10.1158/0008-5472.can-12-3349
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发表时间：
2013-03-01
期刊：
影响因子：
11.2
通讯作者：
Wicha MS
中科院分区：
文献类型：
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作者：
Ithimakin S;Day KC;Malik F;Zen Q;Dawsey SJ;Bersano-Begey TF;Quraishi AA;Ignatoski KW;Daignault S;Davis A;Hall CL;Palanisamy N;Heath AN;Tawakkol N;Luther TK;Clouthier SG;Chadwick WA;Day ML;Kleer CG;Thomas DG;Hayes DF;Korkaya H;Wicha MS
尽管目前的乳腺癌治疗指南限制了HER2阻断剂对HER2基因扩增肿瘤的使用，但最近的回顾性分析表明，更广泛的患者群体可能从这种治疗中受益。利用乳腺癌细胞系，小鼠异种移植模型和匹配的人类原发性和转移性组织，我们证明了HER2在ER+，HER2−管腔乳腺癌中选择性表达并调节癌症干细胞群的自我更新。尽管曲妥珠单抗对已建立的管腔型乳腺癌小鼠异种移植物的生长没有影响，但肿瘤接种后给药可阻断随后的肿瘤生长。与匹配的原发性肿瘤相比，在小鼠骨异种移植物中生长的管腔肿瘤以及乳腺癌患者的骨转移中HER2表达增加。此外，HER2蛋白表达的增加不是由于基因扩增，而是由骨微环境中的RANK配体介导的。这些研究表明，辅助曲妥珠单抗的临床疗效可能与该药物在不需要HER2基因扩增的过程中靶向癌症干细胞群的能力有关。此外，这些研究支持癌症干细胞模型，其中当在辅助环境中施用癌症干细胞靶向剂时实现最大临床益处。
Although current breast cancer treatment guidelines limit the use of HER2 blocking agents to tumors with HER2 gene amplification, recent retrospective analyses suggest that a wider group of patients may benefit from this therapy. Utilizing breast cancer cell lines, mouse xenograft models and matched human primary and metastatic tissues, we demonstrate that HER2 is selectively expressed in and regulates self-renewal of the cancer stem cell population in ER+, HER2− luminal breast cancers. Although trastuzumab had no effects on the growth of established luminal breast cancer mouse xenografts, administration after tumor inoculation blocked subsequent tumor growth. HER2 expression is increased in luminal tumors grown in mouse bone xenografts, as well as in bone metastases from breast cancer patients compared to matched primary tumors. Furthermore this increase in HER2 protein expression was not due to gene amplification but rather was mediated by RANK-ligand in the bone microenvironment. These studies suggest that the clinical efficacy of adjuvant trastuzumab may relate to the ability of this agent to target the cancer stem cell population in a process that does not require HER2 gene amplification. Furthermore these studies support a cancer stem cell model in which maximal clinical benefit is achieved when cancer stem cell targeting agents are administered in the adjuvant setting.