Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.
Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.
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DOI：
10.1530/erc-10-0262
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发表时间：
2011-06
影响因子：
3.9
通讯作者：
Knudsen ES
中科院分区：
文献类型：
--
作者：
Thangavel C;Dean JL;Ertel A;Knudsen KE;Aldaz CM;Witkiewicz AK;Clarke R;Knudsen ES
大多数雌激素受体（ER）阳性乳腺癌均采用内分泌治疗。虽然这很有效，但针对 ER 的治疗获得性耐药是一个重大的临床挑战。在这里，采用对内分泌治疗具有不同敏感性的 ER 阳性乳腺癌模型系统来定义新治疗干预措施的共同节点。这些分析表明，在这些模型中，细胞周期进展与 ER 的活性和功能状态有效脱钩。在这种情况下，即使用纯拮抗剂有效消融 ER，细胞周期蛋白 D1 表达和视网膜母细胞瘤肿瘤抑制蛋白 (RB) 磷酸化仍得以维持。这些治疗抵抗模型概括了 RB/E2F 转录控制失调的一个关键特征。相应地，RB 功能障碍的基因表达特征与管腔 B 型乳腺癌相关，后者对内分泌治疗的反应相对较差。这些共同发现表明，抑制细胞周期蛋白 D 支持的激酶活性和恢复 RB 介导的转录抑制可能代表对激素疗法无效的肿瘤的可行治疗选择。与这一假设一致，高度选择性的 CDK4/6 抑制剂 PD-0332991 可有效抑制所分析的所有激素难治性模型的增殖。重要的是，PD-0332991 导致稳定的细胞周期停滞，这与 ER 拮抗剂引起的细胞周期停滞根本不同，并且能够在激素治疗难治性细胞群中诱导细胞衰老。这些发现强调了下游细胞抑制疗法在治疗内分泌治疗失败的肿瘤中的临床效用。
The majority of estrogen receptor (ER)-positive breast cancers are treated with endocrine therapy. While this is effective, acquired resistance to therapies targeted against ER is a major clinical challenge. Here, model systems of ER-positive breast cancers with differential susceptibility to endocrine therapy were employed to define common nodes for new therapeutic interventions. These analyses revealed that cell cycle progression is effectively uncoupled from the activity and functional state of ER in these models. In this context, cyclin D1 expression and retinoblastoma tumor suppressor protein (RB) phosphorylation are maintained even with efficient ablation of ER with pure antagonists. These therapy-resistant models recapitulate a key feature of deregulated RB/E2F transcriptional control. Correspondingly, a gene expression signature of RB-dysfunction is associated with luminal B breast cancer, which exhibits a relatively poor response to endocrine therapy. These collective findings suggest that suppression of cyclin D-supported kinase activity and restoration of RB-mediated transcriptional repression could represent a viable therapeutic option in tumors that fail to respond to hormone-based therapies. Consistent with this hypothesis, a highly selective CDK4/6 inhibitor, PD-0332991, was effective at suppressing the proliferation of all hormone refractory models analyzed. Importantly, PD-0332991 led to a stable cell cycle arrest that was fundamentally distinct from those elicited by ER antagonists, and was capable of inducing aspects of cellular senescence in hormone therapy refractory cell populations. These findings underscore the clinical utility of downstream cytostatic therapies in treating tumors that have experienced failure of endocrine therapy.