Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan.
Cancer Sci. 2024 May;115(5):1576-1586. doi: 10.1111/cas.16122. Epub 2024 Mar 11.
While loss of function (LOF) of retinoblastoma 1 (RB1) tumor suppressor is known to drive initiation of small-cell lung cancer and retinoblastoma, RB1 mutation is rarely observed in breast cancers at their initiation. In this study, we investigated the impact on untransformed mammary epithelial cells given by RB1 LOF. Depletion of RB1 in anon-tumorigenic MCF10A cells induced reversible growth arrest (quiescence) featured by downregulation of multiple cyclins and MYC, upregulation of p27, and lack of expression of markers which indicate cellular senescence or epithelial-mesenchymal transition (EMT). We observed a similar phenomenon in human mammary epithelial cells (HMEC) as well. Additionally, we found that RB1 depletion attenuated the activity of RAS and the downstream MAPK pathway in an RBL2/p130-dependent manner. The expression of farnesyltransferase β, which is essential for RAS maturation, was found to be downregulated following RB1 depletion also in an RBL2/p130-dependent manner. These findings unveiled an unexpected mechanism whereby normal mammary epithelial cells resist to tumor initiation upon RB1 LOF.
已知视网膜母细胞瘤 1（RB1）肿瘤抑制因子失活会导致小细胞肺癌和视网膜母细胞瘤的发生，但在乳腺癌起始时很少观察到 RB1 突变。在这项研究中，我们研究了 RB1 失活对未转化的乳腺上皮细胞的影响。在非致瘤性 MCF10A 细胞中，RB1 的缺失诱导了可逆的生长停滞（静止），其特征是多个细胞周期蛋白和 MYC 的下调、p27 的上调以及表示细胞衰老或上皮-间充质转化（EMT）的标志物表达缺失。我们在人乳腺上皮细胞（HMEC）中也观察到了类似的现象。此外，我们发现 RB1 缺失以 RBL2/p130 依赖的方式减弱了 RAS 和下游 MAPK 途径的活性。RB1 缺失后，RAS 成熟所必需的法呢基转移酶 β 的表达也以 RBL2/p130 依赖的方式下调。这些发现揭示了一种意想不到的机制，即正常乳腺上皮细胞在 RB1 失活时抵抗肿瘤起始。
