The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS20, 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. FRS2 beta 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 FRS2 beta-deficient premalignant tissues. We found that colocalization of FRS2 beta and the NEMO subunit of the I kappa B kinase complex in early endosomes led to activation of nuclear factor-KB (NF-kappa B), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-kappa B-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2 beta contain more stroma. The elucidation of the FRS2 beta-NF-kappa B axis uncovers a molecular link between the proinflammatory changes and the disease onset.

Automated summary

Adaptor protein FRS20 induces proinflammatory changes in premalignant mammary tissues and is responsible for disease onset, while the FRS2 beta-NF-kappa B axis reveals the molecular link between inflammation changes and tumorigenesis.