Department of Cancer and DNA Damage Responses, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley.
Cancer Res. 2013 Jun 15;73(12):3737-48. doi: 10.1158/0008-5472.CAN-12-3537. Epub 2013 Apr 10.
β1-integrin induction enhances breast cancer cell survival after exposure to ionizing radiation (IR), but the mechanisms of this effect remain unclear. Although NF-κB initiates prosurvival signaling pathways post-IR, the molecular function of NF-κB with other key elements in radioresistance, particularly with respect to extracellular matrix-induced signaling, is not known. We discovered a typical NF-κB-binding site in the β1-integrin promoter region, indicating a possible regulatory role for NF-κB. Using three-dimensional laminin-rich extracellular matrix (3D lrECM) culture, we show that NF-κB is required for β1-integrin transactivation in T4-2 breast cancer cells post-IR. Inhibition of NF-κB reduced clonogenic survival and induced apoptosis and cytostasis in formed tumor colonies. In addition, T4-2 tumors with inhibition of NF-κB activity exhibit decreased growth in athymic mice, which was further reduced by IR with downregulated β1-integrin expression. Direct interactions between β1-integrin and NF-κB p65 were induced in nonmalignant breast epithelial cells, but not in malignant cells, indicating context-specific regulation. As β1-integrin also activates NF-κB, our findings reveal a novel forward feedback pathway that could be targeted to enhance therapy.
β1 整合素的诱导增强了乳腺癌细胞在暴露于电离辐射 (IR) 后的存活能力，但这种效应的机制仍不清楚。虽然 NF-κB 在 IR 后启动了促生存信号通路，但 NF-κB 与其他耐辐射关键因素（特别是与细胞外基质诱导信号相关的因素）的分子功能尚不清楚。我们在 β1 整合素启动子区域发现了一个典型的 NF-κB 结合位点，表明 NF-κB 可能具有调节作用。使用三维层粘连蛋白丰富的细胞外基质 (3D lrECM) 培养，我们表明 NF-κB 是 T4-2 乳腺癌细胞在 IR 后 β1 整合素反式激活所必需的。NF-κB 的抑制降低了集落形成存活能力，并诱导了已形成的肿瘤集落中的细胞凋亡和细胞停滞。此外，NF-κB 活性抑制的 T4-2 肿瘤在无胸腺小鼠中的生长减少，而通过下调 β1 整合素表达与 IR 联合作用则进一步减少了肿瘤生长。非恶性乳腺上皮细胞中诱导了 β1 整合素和 NF-κB p65 之间的直接相互作用，但在恶性细胞中没有，这表明存在特定于上下文的调节。由于 β1 整合素也激活了 NF-κB，我们的发现揭示了一种新的正向反馈途径，可作为增强治疗的靶点。
