Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2β, an adaptor protein expressed in a small subset of epithelial cells, triggers the proinflammatory changes that induce stroma in premalignant mammary tissues and is responsible for the disease onset. FRS2β deficiency in mouse mammary tumor virus (MMTV)–ErbB2 mice markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient premalignant tissues. We found that colocalization of FRS2β and the NEMO subunit of the IκB kinase complex in early endosomes led to activation of nuclear factor–κB (NF-κB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-κB–induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. The elucidation of the FRS2β–NF-κB axis uncovers a molecular link between the proinflammatory changes and the disease onset.

尽管有人认为促炎变化先于乳腺癌的发生，但其潜在机制仍不清楚。在这里，我们证明 FRS2β，一种在一小部分上皮细胞中表达的衔接蛋白，触发促炎变化，诱导癌前乳腺组织中的基质，并导致疾病发作。小鼠乳腺肿瘤病毒 (MMTV)-ErbB2 小鼠中的 FRS2β 缺陷显着减弱了肿瘤发生。重要的是，来自 MMTV-ErbB2 小鼠的肿瘤细胞在移植到 FRS2β 缺陷的癌前组织时未能产生肿瘤。我们发现早期内体中 FRS2β 和 IκB 激酶复合体的 NEMO 亚基的共定位导致核因子-κB (NF-κB) 的激活，这是炎症的主要调节因子。此外，抑制 NF-κB 诱导的细胞因子的活性，CXC 趋化因子配体 12 和胰岛素样生长因子 1，消除了肿瘤发生。表达更高水平 FRS2β 的人乳腺癌组织含有更多的基质。FRS2β-NF-κB 轴的阐明揭示了促炎变化与疾病发作之间的分子联系。