[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-372772-105":59,"doc-detail-372772-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","advances-in-the-intrinsic-signaling-pathway-interactions-and-clinical-translation-of-hrher2-breast-cancer","Advances in the intrinsic signaling pathway interactions and clinical translation of HR+/HER2+ breast cancer","","Hormone receptor-positive (HR+) and HER2-positive (HER2+) breast cancers form a biologically distinct subgroup defined by co-expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, often driving aggressive growth and higher recurrence. These tumors leverage estrogen and HER2-driven signaling to enhance proliferation, survival, and metastatic potential, while treatment faces frequent resistance. Current therapy integrates endocrine approaches with HER2-targeted agents to suppress both axes, yet resistance emerges via mechanisms such as PIK3CA mutations, ER–HER2 cross-talk, and alternative pathway activation. The review outlines molecular foundations, treatment strategies, and emerging combinations including CDK4/6 and PI3K/AKT/mTOR inhibitors to support personalized, adaptive management.",{"@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/advances-in-the-intrinsic-signaling-pathway-interactions-and-clinical-translation-of-hrher2-breast-cancer/372772/",{"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/advances-in-the-intrinsic-signaling-pathway-interactions-and-clinical-translation-of-hrher2-breast-cancer/372772.png","ImageObject",300,407,{"name":92,"@type":93},"Anna Hans","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What makes HR+/HER2+ breast cancer biologically distinct?","Question",{"text":112,"@type":113},"It is characterized by co-expression of ER, PR, and HER2, leading to molecular features that often produce aggressive growth and higher recurrence.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do current treatment strategies address HR+/HER2+ breast cancer?",{"text":117,"@type":113},"They combine endocrine therapies targeting ER/PR signaling with HER2-targeted therapies such as trastuzumab, pertuzumab, or tyrosine kinase inhibitors.",{"name":119,"@type":110,"acceptedAnswer":120},"What are key mechanisms behind resistance in HR+/HER2+ breast cancer?",{"text":121,"@type":113},"Resistance can develop through PIK3CA mutations, cross-talk between ER and HER2 signaling, and activation of alternative growth pathways.","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},372772,1790621428,{"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":44,"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},5909892332657,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Breast Cancer (2025) 32:1216–1243  \n[https://doi.org/10.1007/s12282-025-01779-3](https://doi.org/10.1007/s12282-025-01779-3)  \nAdvances in the intrinsic signaling pathway interactions and clinical translation of HR+/HER2+ breast cancer  \nXinyu Li1 · Tao Huang1  \nReceived: 8 July 2025 / Accepted: 13 September 2025 / Published online: 22 September 2025 © The Author(s) 2025  \nAbstract  \nHormone receptor-positive (HR +) and HER2-positive (HER2+) breast cancers represent a biologically unique subset of breast malignancies characterized by the co-expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2) . These cancers exhibit distinct molecular features, often leading to aggressive growth and higher recurrence rates. HR+/HER2+ breast cancer cells can utilize estrogen and HER2-driven signaling pathways to promote proliferation, survival, and metastatic potential, presenting unique challenges and opportunities for treatment. The current therapeutic strategies focus on a combination of endocrine therapies, such as selective estrogen receptor modulators (e.g., tamoxifen) or aromatase inhibitors, with HER2-targeted therapies like trastuzumab, pertuzumab, or tyrosine kinase inhibitors, to concurrently inhibit both hormone and HER2-driven pathways. Despite initial treatment efficacy, resistance often develops through various mechanisms, including mutations in the PIK3CA gene, cross-talk between ERand HER2 signaling, and activation of alternative growth pathways. Ongoing research aims to improve patient outcomes by exploring novel combination therapies, including CDK4/6 inhibitors and PI3K/AKT/mTOR pathway inhibitors, and by targeting resistance pathways. This review highlights the molecular basis, treatment approaches, and emerging therapeutic strategies in HR+/HER2+ breast cancer, emphasizing the need for personalized and adaptive treatment strategies in managing this complex disease subtype.  \nKeywords Breast cancer · HER2 · Estrogen receptor · Target therapy · Endocrine therapy · Crosstalk  \nIntroduction  \nEstrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are three key biomarkers used to classify breast cancer into four major molecular subtypes based on their expression levels [1] . The Luminal A and Luminal B subtypes, characterized by high hormone receptor expression, are typically responsive to hormone therapies that target the ER/PR signaling pathway. In contrast, the HER2-enriched subtype can be effectively treated with HER2-targeted therapies. Notably, HR-positive/ HER2-positive breast cancer represents a distinct category due to the co-expression of ER (with or without PR) and  \n* Tao Huang [huangtaowh@163.com](huangtaowh@163.com)  \n1 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Rd., Wuhan 430022, People’s Republic of China  \nHER2, differing from classical HER2-enriched or Luminal subtypes.  \nHR+/HER2+ breast cancer accounts for approximately 10–11% of all BC cases, representing 15% of Luminal BC and 70% of HER2-positive BC [2–4] . In addition to distinct biological features, HR+/HER2+ tumors exhibit unique clinicopathological characteristics compared with other subtypes. For instance, patients with HR+/HER2+ BC are more frequently diagnosed at a younger age and with more advanced disease [4] . According to the Surveillance, Epidemiology, and End Results (SEER) registry, the survival outcomes of HR+/HER2+ BC fall between those of HR+/ HER2− and HR−/HER2+ subtypes, suggesting an intermediate prognosis [5] . Furthermore, the therapeutic response to HER2-targeted therapy differs by HR status, with lower efficacy observed in HR+ compared to HR− tumors [6 , 7] . Notably, in both neoadjuvant and metastatic settings, the overall response rate (ORR) is significantly higher in HR− patients, though this does not necessarily trans","cbCaiaPIYiErCk8G","https://ap.wps.com/l/cbCaiaPIYiErCk8G","pdf",1168086,28,"English","# Abstract\n# Introduction\n# Overview of HER2 and ER signaling pathway\n## HER2 signaling pathway","[{\"question\":\"What makes HR+/HER2+ breast cancer biologically distinct?\",\"answer\":\"It is characterized by co-expression of ER, PR, and HER2, leading to molecular features that often produce aggressive growth and higher recurrence.\"},{\"question\":\"How do current treatment strategies address HR+/HER2+ breast cancer?\",\"answer\":\"They combine endocrine therapies targeting ER/PR signaling with HER2-targeted therapies such as trastuzumab, pertuzumab, or tyrosine kinase inhibitors.\"},{\"question\":\"What are key mechanisms behind resistance in HR+/HER2+ breast cancer?\",\"answer\":\"Resistance can develop through PIK3CA mutations, cross-talk between ER and HER2 signaling, and activation of alternative growth pathways.\"}]","Advances in the intrinsic signaling pathway interactions and clinical translation of HR+/HER2+ breast cancer | PDF",1790195334,71]