Abstract 2673: The cytoplasmic adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis

It is widely held that pro-inflammatory changes often precede the onset of breast cancer. However, the underlying molecular mechanisms are largely unknown. Here, we demonstrate that FRS2β, a membrane-linked adaptor protein expressed in a small subset of luminal epithelial cells, triggers the inflammatory changes in precancerous mammary tissues and is responsible for the onset of the disease. FRS2β-deficiency in a mouse mammary tumor virus (MMTV)-ErbB2 genetic background markedly attenuated mammary tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2β-deficient precancerous mammary tissue niche. we observed that the co-localization of FRS2β and the NEMO subunit of the IκB kinase (IKK) complex on early endosomes led to activation of nuclear factor-κB (NFκB). Moreover, the expression of numerous cytokines, including CXC chemokine ligand (CXCL)12, was elevated owing to the activation of NFκB. CXCL12 may in turn activate NFκB in an autocrine and paracrine loop, leading to the inflammatory changes that promote tumorigenesis. The elucidation of the FRS2β-dependent NFκB-activation pathway uncovers a hitherto unknown molecular link between the tissue inflammation and the onset of breast cancer. Citation Format: Noriko Gotoh, Yasuto Takeuchi, Natsuko Kimura, Takehiko Murayama, Yukino Machida, Daisuke Iejima, Tatsunori Nishimura, Mizuki Yamamoto, Jun-ichito Inoue, Kouichi Akashi, Hideyuki Saya, Masahiko Kuroda, Issay Kitabayashi, Arinobu Tojo. The cytoplasmic adaptor FRS2beta fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2673.