Signaling Networks Involved in the Malignant Transformation of Breast Cancer

Breast cancer stem cells (CSCs) are involved the malignant transformation of breast cancer, including metastasis, because they are more stress-resistant and have higher tumorigenicity than the surrounding breast cancer cells (non-CSCs). We aimed to elucidate the various signaling networks involved in the transformation of mammary epithelial cells into tumor cells based on literature review. We found that constitutive activation of the NF-\({\upkappa}{\text{B}}\) pathway maintains CSCs in basal-like breast cancer, a subtype of triple-negative breast cancer, where NF-\({\upkappa}{\text{B}}\)-mediated induction of JAG1 in non-CSCs results in the stimulation of Notch signaling in CSCs. On the other hand, epithelial-mesenchymal transition (EMT) and its reverse reaction, mesenchymal-epithelial transition (MET), are thought to be involved in breast cancer cell metastasis, which makes elucidating their regulatory mechanisms essential. We identified HCC38, a basal-like breast cancer cell line, as a suitable model to investigate such mechanisms, because EMT and MET are in intratumoral equilibrium with each other in HCC38. In the HCC38 study, we found that multiple signaling pathways between epithelial and mesenchymal cells are involved in the regulation of the dynamic equilibrium between EMT and MET. Mathematical simulation of these intracellular and intercellular signaling networks involved in the malignant transformation of breast cancer could lead to the elucidation of the mechanisms of tumor malignant transformation and the development of therapeutic targets.