細胞質アダプタータンパクFRS2βは，乳がん形成を促進する 炎症性サイトカインリッチ環境を形成する

抄録

Although it is held that pro-infl ammatory 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 mammary epithelial cells, triggers the pro-inflammatory changes that induce stroma in precancerous mammary tissues and is responsible for the disease onset. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 genetic background markedly attenuated mammary tumorigenesis. FRS2β (+/+) tumors contained ample stroma, on the other hand, very little stroma was observed in FRS2β (-/-) tumors, suggesting that FRS2β is required for the formation of tumor stroma. Tumor cells derived from MMTV-ErbB2 mice failed to form tumors when they were inoculated in the FRS2β-defi cient precancerous mammary tissues, indicating that FRS2β plays essential role in mammary tumorigenesis. We also demonstrated that co-localization of FRS2β and the NEMO subunit of the IkB kinase (IKK) complex in early endosomes led to activation of nuclear factor-κB (NF-κB), a master regulator of infl ammation. Moreover, inhibition of the activities of the NF-κB-induced cytokines, CXC chemokine ligand (CXCL)12 and insulin-like growth factor (IGF)1, abrogated tumorigenesis, indicating that the production of IGF1 and CXCL12 in premalignant mammary tissues creates a cytokine-enriched microenvironment that is necessary for mammary tumorigenesis. Human breast cancer tissues that express higher levels of FRS2β contain more stroma. Furthermore, patients with higher expression levels of FRS2βin breast cancer tissues had poorer prognosis. Collectively, the elucidation of the FRS2β-NF-κB axis uncovers the unknown molecular link between the pro-infl ammatory changes and the onset of breast cancer.