Inflammatory cytokine‐enriched microenvironment plays key roles in the development of breast cancers

Abstract

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 into 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 is still an unmet need to diagnose malignant DCIS, which has the potential to progress to IBC, and to establish appropriate prevention strategies. We recently demonstrated novel molecular mechanisms for NF‐κB activation in premalignant mammary tissues, which include DCIS, and the 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 is necessary to prevent the risk of IBC.

Epistemology of the Origin of Cancer II: Fibroblasts Are the First Cells to Undergo Neoplastic Transformation

“…CAFs have also been identified in precancerous lesions of the blood, for example, monoclonal gammopathy of unknown significance [181][182][183] and the breast. Tenascin, which is a marker for CAFs [184], has also been detected in precancerous breast lesions as well as in ductal or lobular carcinoma in situ [185][186][187][188][189][190][191][192][193].…”

Targeting Store-Operated Calcium Entry Regulates the Inflammation-Induced Proliferation and Migration of Breast Cancer Cells

“…One of these proteins is the Vascular Endothelial Growth Factor (VEGF), which has been previously reported to enhance the migration and invasion of breast cancer [ 3 ]. Inflammation is another factor that influences the progression of breast cancer, adding to the complexity of breast cancer therapy [ 4 , 5 ].…”