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This study tested lasofoxifene (LAS), alone or with palbociclib, in a letrozole-resistant breast tumor model lacking ESR1 mutations. In xenografts, LAS ± palbociclib reduced primary tumor growth, decreased proliferation markers, and lowered bone metastases. Results support LAS ± CDK4/6 inhibition for ER-low, HER2-positive, AI-resistant disease independent of ESR1 status.",{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lasofoxifene-as-a-potential-treatment-for-aromatase-inhibitor-resistant-er-positive-breast-cancer/342892/",{"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/lasofoxifene-as-a-potential-treatment-for-aromatase-inhibitor-resistant-er-positive-breast-cancer/342892.png","ImageObject",300,407,{"name":92,"@type":93},"Violet","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why does aromatase inhibitor therapy lead to resistance in ER-positive breast cancer?","Question",{"text":112,"@type":113},"Resistance can develop through ESR1 (ERα) activating mutations and through ER-independent signaling pathways that bypass estrogen-deprivation effects.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What animal and cell model was used to test lasofoxifene?",{"text":117,"@type":113},"Letrozole-resistant MCF7 LTLT cells expressing luciferase-GFP were injected into NSG mouse mammary duct inguinal glands, and mice were randomized to treatment groups.",{"name":119,"@type":110,"acceptedAnswer":120},"What were the main findings for lasofoxifene alone versus with palbociclib?",{"text":121,"@type":113},"Lasofoxifene plus palbociclib significantly reduced primary tumor growth compared with vehicle, lowered overall proliferation, and reduced bone metastases; similar results were observed in a repeat experiment.","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},342892,1790168251,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":44,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},4398048950312,"https://ap-avatar.wpscdn.com/avatar/400002538284de19e3c?_k=1778320343897328908","Lainé et al. Breast Cancer Research (2024) 26:95 Breast Cancer Research  \n[https://doi.org/10.1186/s13058-024-01843-4](https://doi.org/10.1186/s13058-024-01843-4)  \nRESEARCH Open Access  \nLasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer  \nMuriel Lainé 1, Marianne E Greene 1, Justyna D Kurleto 1, Grazyna Bozek 1, Tiffany Leng 1, Rosemary J Huggins 1, Barry S Komm2 and Geoffrey L Greene 1*  \nAbstract  \nBackground Breast cancers treated with aromatase inhibitors (AIs) can develop AI resistance, which is often driven by estrogen receptor-alpha (ERα/ESR1) activating mutations, as well as by ER-independent signaling pathways. The breast ER antagonist lasofoxifene, alone or combined with pal bociclib, elicited antitumor activities in a xenograft model of ER + metastatic breast cancer (mBC) harboring ESR1 mutations. The current study investigated the activity of LAS in a letrozole-resistant breast tumor model that does not have ESR1 mutations.  \nMethods Letrozole-resistant, MCF7 LTLT cells tagged with luciferase-GFP were injected into the mammary  \nduct inguinal glands of NSG mice (MIND model; 6 mice/group) . Mice were randomized to vehicle,  \nlasofoxifene ± pal bociclib, fulvestrant ± pal bociclib, or pal bociclib alone 2–3 weeks after cell injections. Tumor growth and metastases were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. The experiment was repeated with the same design and 8–9 mice in each treatment group.  \nResults Western blot analysis showed that the MCF7 LTLT cells had lower ERα and higher HER2 expressions compared with normal MCF7 cells. Lasofoxifene ± pal bociclib, but not fulvestrant, significantly reduced primary tumor growth versus vehicle as assessed by in vivo imaging of tumors at study ends. Percent tumor area in excised mammary glands was significantly lower for lasofoxifene plus pal bociclib versus vehicle. Ki67 staining showed decreased overall tumor cell proliferation with lasofoxifene ± pal bociclib. The lasofoxifene + pal bociclib combination was also associated with significantly fewer bone metastases compared with vehicle. Similar results were observed in the repeat experiment.  \nConclusions In a mouse model of letrozole-resistant breast cancer with no ESR1 mutations, reduced levels of ERα, and overexpression of HER2, lasofoxifene alone or combined with pal bociclib inhibited primary tumor growth more effectively than fulvestrant. Lasofoxifene plus pal bociclib also reduced bone metastases. These results suggest that lasofoxifene alone or combined with a CDK4/6 inhibitor may offer benefits to patients who have ER-low and HER2-positive, AI-resistant breast cancer, independent of ESR1 mutations.  \n*Correspondence: Geoffrey L Greene[ggreene@uchicago.edu](ggreene@uchicago.edu)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.","cbCairrBvdgdeai7","https://ap.wps.com/l/cbCairrBvdgdeai7","pdf",1656307,"English","# Abstract\n# Background\n# Methods\n# Results\n# Conclusions\n# Keywords\n# Introduction","[{\"question\":\"Why does aromatase inhibitor therapy lead to resistance in ER-positive breast cancer?\",\"answer\":\"Resistance can develop through ESR1 (ERα) activating mutations and through ER-independent signaling pathways that bypass estrogen-deprivation effects.\"},{\"question\":\"What animal and cell model was used to test lasofoxifene?\",\"answer\":\"Letrozole-resistant MCF7 LTLT cells expressing luciferase-GFP were injected into NSG mouse mammary duct inguinal glands, and mice were randomized to treatment groups.\"},{\"question\":\"What were the main findings for lasofoxifene alone versus with palbociclib?\",\"answer\":\"Lasofoxifene plus palbociclib significantly reduced primary tumor growth compared with vehicle, lowered overall proliferation, and reduced bone metastases; similar results were observed in a repeat experiment.\"}]","Lasofoxifene as a potential treatment for aromatase inhibitor-resistant ER-positive breast cancer | PDF",1790048666,23]