Breast cancer is a significant global concern,with limited effective treatment options.Therefore,therapies with high efficacy and low complications,unlike the existing chemotherapies,are urgently required.To address this issue,advances have been made in therapies targeting molecular pathways related to the murine double minute 2 protooncogene(MDM2)-tumor proteinp53(TP53)interaction.This review aims to investigate the efficacy of MDM2 inhibition in restoring TP53 activity in breast cancer cells,as evidenced by clinical studies,reviews,and trials.TP53 is a tumor suppressor and MDM2 facilitates proteasomal degradation of TP53.MDM2 and TP53 activity is tightly regulated.However,cancerous breast cells overexpress MDM2 through five hypothesized mechanisms.Consequently,TP53 levels decrease with increased tumor cell proliferation.Three strategies have been identified for controlling MDM2 upregulation in cells with wild-type or mutated TP53.MDM2 inhibitors(MDM2i)are administered in combination with existing chemotherapies to reduce their effects on healthy cells.Few clinical and preclinical studies have been conducted using MDM2i,which necessitates high-quality clinical trials to support their therapeutic potential in breast cancer therapy.
Targeting oncogenes and their interactive partners is an effective approach to developing novel targeted therapies for cancer and other chronic diseases.We and others have long suggested the MDM2 oncogene being an excellent target for cancer therapy,based on its p53-dependent and-independent oncogenic activities in a variety of cancers.The MYC family proteins are transcription factors that also regulate diverse biological functions.Dysregulation of MYC,such as amplification of MYCN,is associated with tumorigenesis,especially for neuro-blastoma.Although the general survival rate of neuroblastoma patients has significantly improved over the past few decades,high-risk neuroblastoma still presents a poor prognosis.Therefore,innovative and more potent therapeutic strategies are needed to eradicate these aggressive neoplasms.This review focuses on the oncogenic properties of MYCN and its molecular regulation and summarizes the major therapeutic strategies being developed based on pre-clinical findings.We also highlight the potential benefits of targeting both the MYCN and MDM2 oncogenes,providing preclinical evidence of the efficacy and safety of this approach.In conclusion,the development of effective small molecules that inhibit both MYCN and MDM2 represents a promising new strategy for the treatment of neuroblastoma and other cancers.
