Key subunits of γ-secretase complex and breast cancer progression: biological function, regulation mode and therapeutic potential

Breast cancer (BC) is the most prevalent malignant tumor among females. The primary therapeutic options currently available include surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. However, the emergence of drug resistance has resulted in a gradual decline in the efficacy of these treatments. The activation of the Notch signaling pathway is closely associated with the development and progression of breast cancer. γ-secretase, a crucial hydrolase in the Notch pathway, consists of four subunits: presenilin 1 and 2 (PSEN1 and 2), presenilin enhancer 2 (PEN-2), Nicastrin (NCSTN), and anterior pharynx defective 1 (APH-1). These subunits interact to maintain the overall biological function and stability of the complex. This review utilizes the key subunits of γ-secretase as a focal point to elucidate the structure-function relationships, interactions, and their relevance to the progression of breast cancer for each complex subunit, and the preclinical studies and clinical trials were discussed, emphasizing the relationship between the key subunits of γ-secretase complex and the pathogenesis of BC. Furthermore, the challenges and prospects of γ-secretase inhibitors as potential therapies for chemoresistance in breast cancer were discussed.