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In breast cancer, p53 function is often lost through MDM2 overexpression or p53 mutations present in roughly 30–35% of cases. Mutation patterns vary by subtype: luminal/hormone-receptor-positive tumors more often retain wild-type p53, whereas hormone-receptor-negative tumors frequently harbor gain-of-function mutant p53, associated with poorer prognosis. The review evaluates emerging p53-targeted therapies across wild-type and mutant contexts, including small molecules, stapled peptides, PROTACs, and genetic vector or engineered antibody approaches, summarizing both pre-clinical and clinical performance, plus limitations.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/role-of-p53-in-breast-cancer-progression-an-insight-into-p53-targeted-therapy/382149/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/role-of-p53-in-breast-cancer-progression-an-insight-into-p53-targeted-therapy/382149.png","ImageObject",300,407,{"name":92,"@type":93},"Jiven","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-24",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How is p53 activated under genotoxic stress, and what outcomes does it promote?","Question",{"text":112,"@type":113},"p53 becomes activated in the presence of genotoxic stress to facilitate DNA repair, cell-cycle arrest, and apoptosis.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why does p53 become inactivated in breast cancer?",{"text":117,"@type":113},"p53 tumor-suppressive activity is frequently inactivated by MDM2 overexpression or by p53 mutation, reported in about 30–35% of breast cancer cases.",{"name":119,"@type":110,"acceptedAnswer":120},"How do p53 mutation frequencies differ across breast cancer subtypes?",{"text":121,"@type":113},"The review reports that p53 mutation frequency is highly subtype dependent: hormone receptor-positive/luminal subtypes often retain wild-type p53, while hormone receptor-negative patients more commonly carry mutant p53 with gain-of-function oncogenic activity and worse prognosis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},382149,1790393167,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","Review  \nIvyspring  \nInternational Publisher  \nTheranostics  \n2023; 13(4): 1421-1442. doi: 10.7150/thno.81847  \nRole of p53 in breast cancer progression: An insight intop53 targeted therapy  \nCharlie Marvalim1􀀍, Arpita Datta1, Soo Chin Lee1,2􀀍  \n1. Cancer Science Institute of Singapore, Singapore 117599, Singapore  \n2. Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore 119228, Singapore  \n􀀍 Corresponding authors: C.M. E-mail: [e0547608@u.nus.edu](e0547608@u.nus.edu); L.S.C. E-mail: [csilsc@nus.edu.sg](csilsc@nus.edu.sg); Tel: (65) 6516 7282  \n© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [http://ivyspring.com/terms](http://ivyspring.com/terms) for full terms and conditions.  \nReceived: 2022.12.14; Accepted: 2023.01.26; Published: 2023.02.27  \nAbstract  \nThe transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.  \nKey words: Breast cancer, wild-type p53, mutant p53, targeted therapy, MDM2  \nIntroduction  \nPhysiological functions of p53 in cancer  \nIntroduction to p53  \nThe tumor suppressor p53 is a major transcription factor involved in the regulation of several cellular functions. In cancer, p53 attenuates cell proliferation in response to various stimuli, including DNA damage, nutrient deprivation, hypoxia, hyperproliferative signals, thereby preventing tumor formation [1] . Thus, it is aptly known as“guardian of the genome”. Under normal physiological conditions, p53 levels are tightly regulated by MDM2, an E3 ligase that triggers p53 degradation through the ubiquitin proteasome-dependent pathway. p53 can also induce MDM2 expression by binding to its promoter. This creates a negative  \nfeedback loop to promote p53 degradation to maintain a low cellular p53 [2] . In the presence of cellular stresses, p53 undergoes a series of posttranslational modifications such as 1) phosphorylation which stabilizes p53 by disrupting its interaction with MDM2, 2) sequence-specific DNA binding, 3) transactivation where p53 activates or represses its target genes involved in the control of cell cycle, DNA repair, and induction of senescence and apoptosis (Figure 1) [3] .  \nIn this article, we will be looking into the involvement of p53 and its mutations in the different processes associated with breast cancer development and review the various therapeutic strategies that are being developed to target wild-type and mutant p53 cancers.  \nFigure 1. Under normal conditi","cbCailde9N3AtorL","https://ap.wps.com/l/cbCailde9N3AtorL","pdf",3520723,22,"English","# Abstract\n# Introduction\n## Physiological functions of p53 in cancer\n### Introduction to p53\n### Functional effects of p53\n## DNA repair\n## Cell cycle regulation\n## Apoptosis\n# Therapeutic strategies targeting p53 in breast cancer","[{\"question\":\"How is p53 activated under genotoxic stress, and what outcomes does it promote?\",\"answer\":\"p53 becomes activated in the presence of genotoxic stress to facilitate DNA repair, cell-cycle arrest, and apoptosis.\"},{\"question\":\"Why does p53 become inactivated in breast cancer?\",\"answer\":\"p53 tumor-suppressive activity is frequently inactivated by MDM2 overexpression or by p53 mutation, reported in about 30–35% of breast cancer cases.\"},{\"question\":\"How do p53 mutation frequencies differ across breast cancer subtypes?\",\"answer\":\"The review reports that p53 mutation frequency is highly subtype dependent: hormone receptor-positive/luminal subtypes often retain wild-type p53, while hormone receptor-negative patients more commonly carry mutant p53 with gain-of-function oncogenic activity and worse prognosis.\"}]","Role of p53 in breast cancer progression - An insight into p53 targeted therapy | PDF",1790249296,55]