| First Author | Takeuchi Y | Year | 2021 |
| Journal | Proc Natl Acad Sci U S A | Volume | 118 |
| Issue | 43 | PubMed ID | 34663724 |
| Mgi Jnum | J:313934 | Mgi Id | MGI:6802159 |
| Doi | 10.1073/pnas.2103658118 | Citation | Takeuchi Y, et al. (2021) The membrane-linked adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis. Proc Natl Acad Sci U S A 118(43):e2103658118 |
| abstractText | Although it is held that proinflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we demonstrate that FRS2beta, 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. FRS2beta 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 FRS2beta-deficient premalignant tissues. We found that colocalization of FRS2beta and the NEMO subunit of the IkappaB kinase complex in early endosomes led to activation of nuclear factor-kappaB (NF-kappaB), a master regulator of inflammation. Moreover, inhibition of the activities of the NF-kappaB-induced cytokines, CXC chemokine ligand 12 and insulin-like growth factor 1, abrogated tumorigenesis. Human breast cancer tissues that express higher levels of FRS2beta contain more stroma. The elucidation of the FRS2beta-NF-kappaB axis uncovers a molecular link between the proinflammatory changes and the disease onset. |
