Exploring TP53 and HER2 Interactions in Breast Cancer: From Genetic Mutations to Therapeutic Resistance
Exploring TP53 and HER2 Interactions in Breast Cancer: From Genetic Mutations to Therapeutic Resistance
Zahra Pirooz,1,*Zahra Mirchi,2
1. Zahra pirooz , Under graduate student in Cellular and Molecular Biology, Faculty of Biological Science, North-Tehran Azad University 2. Zahra Mirchi, Under graduate student in Cellular and Molecular Biology, Faculty of Biological Science , North-Tehran Azad University
Introduction: Uncontrolled mammary epithelial cell development causes breast cancer for several reasons. Several genes that cause mutations concurrently cause cellular cancer. Cancer can result from many mutations. Mutations raise cancer phenotypic complexity and treatment difficulty. These are frequent breast cancer mutations:TP53-PIK3CA_HER2_BRCA1_BRCA2,base on Gene expression pattern classifies breast cancer as: luminal (A and B), Basal like, Normal like, Her2 positive. P53 mutation is lowest in luminal, Mostly p53 mutations. Base like In more than half of HER2-type proliferative tumors, p53 mutations are present, and HER2 overexpression is associated with a worse prognosis. combines We examine these two's effects and therapy in recent publications.
Background: A 1979 study found p53 participation in the cell cycle and cancer cell invasion and metastasis.HER2 discovery in1985, These studies linked p53 and HER2 to aggressive cancers, notably breast cancer. It led to making important drugs like trastuzumab , Her2(ErbB2)is a tyrosine kinase receptor with inactive membrane monomers that promotes cell growth and survival. HER2-positive breast cancer accounts for 10-15% . 30 to 40% of breast cancer patients with higher HER2 levels also have high estrogen receptor levels, which worsens prognosis due to high and early recurrence and metastatic potential. Breast cancer cells overexpressing HER2 proliferate aggressively and have poor prognosis. Her2 mutation drives advanced breast cancer The tumor suppressor P53 is encoded by TP53. Over 50% of neoplasm related mutations include p53 mutation the important role of p53 is regulating the cell cycle, proliferation, senescence, apoptosis, metabolism in response to cellular stress, this protein
protects genetic integrity. particularly in breast cancer, most typically modify this suppressor's gene because it inhibits carcinogenesis. About a third of TP53 point mutations change amino acids in these locations:R175_G245_R248_R249_R273_R282_ Spots of p53 DNA domain mutations. The DNA sequence is directly affected by mutations like R248_R273. Other types include as R175 structural
mutations: P53R273C_P53R248Q Two TP53 gene variations create P53. Point mutations make p53 bind or negatively affect dominantly- Gain of function increases carcinogenesis, independent cell proliferation, chemotherapeutic sensitivity, metastasis, invasion, spindle checkpoint disruption, topoisomerase activity, and gene replication. The E3 ligase MDM-2, which prevents p-53 gene activation, controls p53 levels and binds to it. Inactivating p53 is frequent with negative regulator overexpression or mutation. The promoter's negative feedback loop lowers p53. Overproducing MDM2 accelerates p53 degradation, allowing uncontrolled cell proliferation. Indeed, p53 dysfunction and HER2 overexpression can abolish p53's repression and enhance HER2. This stimulates tumor development and survival. HER2 signals alter p53 stability and function. Due to p53 mutations changing HER2 expression, the tumor microenvironment changes p53-HER2 interactions. According to the study, mutant p53 (p53R175H) stabilizes HER2.It can transcribe EGFK and stabilize HER2, and both mutants P53R248Q and P53R273C acetylate histones H3 and H4 at the promoter, becoming proximal to HER2. These mutations increase HER2 in cell lines.
Methods: Since this is a review article we are working on the interaction between P53 and HER2 and targeted therapy.
Results: some of Working breast cancer treatments: trastuzumab Monoclonal antibody inhibits HER2 signaling To inhibit homodimerization and overexpression, trastuzumab binds to the HER2e ectodomain. The medicine pertuzumab is effective too. This monoclonal antibody inhibits dimer formation with other HER2 receptors by binding to HER2.Recent drugs that target HER2 and other cancer cell proteins are more effective. Research tries to destroy cancer cells with immunotherapy and Her2-targeted treatments. The trastuzumab-chemotherapy combination T-DM1 also works for HER2 cancer. Checkpoint
inhibitors PD-1/PD-L1 Breast cancer clinical studies show significant improvements. New breast cancer treatments include TKIs, tumor vaccines, and adoptive T-cell immunotherapies. Nice breast cancer results Lapatinib TKI targets Her1 and Her2, It substantially blocks lapatinib's ATP binding pocket. Blocking receptor phosphorylation inhibits downstream processes, Prevents MAPK/Erk1/2/PI3K/AKT .Here are P53-based treatments: A unique small-molecule chemical inhibitor, stapled peptide, PROTAcs, and GE vectors and antibodies.
Conclusion: Recent research shows that understanding mutation connections that promote cancer cells is essential to treat it. The processes controlling these components' interactions can be studied to improve breast cancer therapies that prevent neoplastic cell invasion and metastasis. Targeting HS90is one of researching studies that Supports P53 folding and HER2 stability, Targeting HS90can prevent signaling path way of HER2and gain of function of mutated P53. Cancer cell treatment with targeted immunotherapy is one of the effective ways and recent research includes adoptive cell treatment, monoclonal antibodies, oncolytic viruses, immune system modulators, and P53-regulates MDM2.more Research on p53 specific mutations that change HER2 activity may prevent cancer cell growth.
Keywords: Targeted therapy-Immunotherapy-p53 muta4ons-Breast cancer-Her2 Over expression