Inflammatory cytokines-enriched microenvironment plays key roles for the development of breast cancers.

As the incidence of breast cancer continues to increase, it is critical to develop prevention strategies for this disease. Inflammation underlies the onset of the disease, and NF-κB is a master transcription factor for inflammation. Nuclear factor-κB (NF-κB) is activated in a variety of cell types, including normal epithelial cells, cancer cells, cancer-associated fibroblasts (CAFs), and immune cells. Ductal carcinoma in situ (DCIS) is the earliest stage of breast cancer, and not all DCIS lesions develop toward invasive breast cancers (IBC). Currently, most patients with DCIS undergo surgery with postoperative therapy, although there is a risk of overtreatment. In BRCA mutants, receptor activator of NF-κB (RANK)-positive progenitors serve as the cell-of-origin, and treatment using the RANK monoclonal antibody reduces the risk of IBC. There are still unmet needs to diagnose malignant DCIS that has the potential to progress to IBC and to establish appropriate prevention strategy. We recently demonstrated novel molecular mechanisms for NF-κB activation in premalignant mammary tissues which include DCIS, and resultant cytokine-enriched microenvironment is essential for breast cancer development. On the early endosomes in a few epithelial cells, the adaptor protein FRS2β, forming a complex with ErbB2, carries the IκB kinase (IKK) complex and leads to the activation of NF-κB, thereby inducing a variety of cytokines. Therefore, the FRS2β-NFκB axis in the inflammatory premalignant environment could be targetable to prevent IBC. Further analysis of the molecular mechanisms of inflammation in the premalignant microenvironment will be needed to prevent the risk of IBC.