Rb驱动的转录限制了其在乳腺癌中的肿瘤抑制作用，这一成果由澳大利亚彼得麦卡勒姆癌症中心Shom Goel小组经过不懈努力而取得。相关论文于2026年8月12日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该研究团队发现CDK4/6抑制诱导低磷酸化Rb重新分配到启动子和增强子。虽然Rb可以与细胞周期基因启动子结合抑制转录，但在其他位点，它通过整合到富含雌激素受体（ER）的转录中心，意想不到地促进了雌激素应答基因的表达。CDK4/6抑制以Rb依赖的方式增强乳腺癌细胞、患者来源的异种移植物和临床HR⁺乳腺癌样本中ER靶基因的表达。这种重编程部分是由KDM5A介导的，它与Rb的相互作用有助于这些位点的基因调控。关键的是，这个Rb驱动的ER转录程序的组成部分是促增殖的。在内分泌敏感的肿瘤中，这种作用可以通过抗雌激素治疗来中和，这解释了治疗的协同作用。在内分泌抵抗的情况下，如ESR1突变乳腺癌，该计划持续存在，限制了CDK4/6抑制的治疗效果。这些发现重新定义了Rb作为一种双重功能的转录调节剂，虽然强制细胞周期阻滞，但也可以激活抵消其肿瘤抑制功能的程序。

据悉，视网膜母细胞瘤蛋白（Rb）是一种肿瘤抑制因子，以抑制E2F转录因子和停止细胞周期进程而闻名。在激素受体阳性（HR⁺）乳腺癌中，CDK4/6抑制剂通过阻止Rb的磷酸化来激活Rb，形成了当前内分泌治疗方案的关键组成部分。药物激活Rb如何重塑染色质并影响细胞周期阻滞以外的转录仍然知之甚少。

附：英文原文

Title: Rb-driven transcription limits its tumour-suppressive effects in breast cancer

Author: Watt, April C., Ahn, Antonio, Blyth, Catherine, Dixon-Douglas, Julia R., Ambani, Krutika, Coulson, Rhiannon, Taylor, Michael, Chan, Keefe T., Dietrich, Catherine, Russ, Brendan E., Ramm, Susanne, Mahendra, Christabella A., Lu, Kun-Hui, Pires, Nichelle, Garcia-Sannicolas, Jesus, Voulgaris, Olivia, Nunag, Sheena, Ang, Ching-Seng, Dawson, Mark A., Lim, Elgene, Arnedos, Monica, Chandarlapaty, Sarat, Andr, Fabrice, Goel, Shom

Issue&Volume: 2026-08-12

Abstract: The retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression1. In hormone receptor-positive (HR+) breast cancer, CDK4/6 inhibitors activate Rb by preventing its phosphorylation, forming a key component of current endocrine therapy regimens2. How pharmacologically activated Rb remodels chromatin and influences transcription beyond cell cycle arrest remains poorly understood. Here we show that CDK4/6 inhibition induces redistribution of hypophosphorylated Rb to promoters and enhancers. Although Rb predictably binds to cell cycle gene promoters to repress transcription, at other sites, it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. CDK4/6 inhibition enhances ER target gene expression in breast cancer cells, patient-derived xenografts and clinical HR+ breast cancer samples in an Rb-dependent manner. This reprogramming is mediated in part by KDM5A, whose interaction with Rb contributes to gene regulation at these loci. Critically, components of this Rb-driven ER transcriptional program are pro-proliferative. In endocrine-sensitive tumours, this effect can be neutralized with anti-oestrogen therapy, explaining therapeutic synergy. In endocrine-resistant settings such as ESR1-mutant breast cancer, the program persists, limiting the therapeutic efficacy of CDK4/6 inhibition. These findings reframe Rb as a dual-function transcriptional regulator that, although enforcing cell cycle arrest, can also activate programs that counteract its tumour suppressor function.

DOI: 10.1038/s41586-026-10886-w

Source: https://www.nature.com/articles/s41586-026-10886-w