The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer
The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer
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DOI：
10.1172/jci28803
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发表时间：
2007-01-01
影响因子：
15.9
通讯作者：
Knudsen, Erik S.
中科院分区：
文献类型：
--
作者：
Bosco, Emily E.;Wang, Ying;Knudsen, Erik S.
视网膜母细胞瘤肿瘤抑制（RB）蛋白在大多数人类癌症中功能失活，并且在三分之一的乳腺癌中异常。RB调节G（1）/S期细胞周期进程，是抗增殖信号传导的关键介质。在这里，RB缺陷对E2 F调节的基因表达，致瘤性增殖，以及对2种不同的治疗线的反应的具体影响在乳腺癌细胞中进行了研究。RB敲低导致RB/E2 F靶基因失调和加速致瘤性增殖，从而证明即使在复杂肿瘤细胞基因组的背景下，RB状态也对增殖发挥显著控制。此外，RB缺乏损害了顺铂、电离辐射和抗雌激素治疗后的短期细胞周期抑制。在DNA损伤剂的情况下，这种旁路导致细胞培养和异种移植模型中对这些试剂的敏感性增加。相反，在他莫昔芬的存在下，抗雌激素信号的旁路导致继续增殖和异种移植肿瘤生长。RB功能异常的这些影响被异位E2 F表达所概括，表明下游靶基因的控制是所观察到的反应的重要决定因素。对60例人类患者RB基因表达特征的特异性分析表明，该途径的失调与他莫昔芬单药治疗后的早期复发相关。因此，由于RB途径是致瘤性增殖和差异治疗反应的关键决定因素，因此它可能代表指导乳腺癌治疗的关键基础。
The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G(1)/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.