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IC50 values were measured with an MTT assay, and resistant cells were generated by stepwise tamoxifen exposure. After nano-curcumin treatment, migration, proliferation, and apoptosis were assessed using wound healing and flow cytometry, while qRT-PCR and Western blot evaluated pathway activity. Nano-curcumin reduced proliferation, viability, and migration and increased apoptosis, lowering Cyclin D1, DILA1, NF-κB, PI3K, AKT, mTOR, VEGFα, MMP2, and BCL2 while increasing PTEN, TIMP3, RECK, and BAX. These results suggest improved tamoxifen response through DILA1 downregulation and PI3K/AKT/mTOR suppression.",{"@graph":69,"@context":123},[70,84,106],{"@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/nano-curcumin-enhances-the-sensitivity-of-tamoxifen-resistant-breast-cancer-cells-via-the-cyclin-d1-dila1-axis-and-the-pi3kaktmtor-pathway-downregulation/373834/",{"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/nano-curcumin-enhances-the-sensitivity-of-tamoxifen-resistant-breast-cancer-cells-via-the-cyclin-d1-dila1-axis-and-the-pi3kaktmtor-pathway-downregulation/373834.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",16,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"How were tamoxifen-resistant MCF-7 cells generated in the study?","Question",{"text":113,"@type":114},"Resistant MCF-7 cells were established by stepwise exposure to tamoxifen, gradually increasing the concentration to twice the IC50 dose.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which assays were used to measure key cellular behaviors after nano-curcumin treatment?",{"text":118,"@type":114},"Cell migration, proliferation, and apoptosis were evaluated using a wound healing assay and flow cytometry.",{"name":120,"@type":111,"acceptedAnswer":121},"What molecular changes did qRT-PCR and Western blot show after nano-curcumin treatment?",{"text":122,"@type":114},"Expression of Cyclin D1, DILA1, NF-κB, PI3K, AKT, mTOR, VEGFα, MMP2, and BCL2 decreased, while PTEN, TIMP3, RECK, and BAX increased.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},373834,1790467811,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"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},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","OPEN ACCESS  \nCitation: Givi T, Mohajerani F, Tehrankhah ZM, Karimi Taheri M, Amirahmadi M, Babashah  \nS, et al. (2025) Nano-curcumin enhances the sensitivity of tamoxifen-resistant breast cancer cells via the Cyclin D1-DILA1 axis and the PI3K/ AKT/mTOR pathway downregulation. PLoS One 20(12): e0335165. [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pone.0335165](journal.pone.0335165)  \nEditor: Partha Mukhopadhyay, National Institutes of Health, UNITED STATES OF AMERICA  \nReceived: April 22, 2025  \nAccepted: October 7, 2025  \nPublished: December 5, 2025  \nPeer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: [https://doi.org/10.1371/journal](https://doi.org/10.1371/journal). pone.0335165  \nCopyright: © 2025 Givi et al. This is an open access article distributed under the terms of  \nRESEARCH ARTICLE  \nNano-curcumin enhances the sensitivity of tamoxifen-resistant breast cancer cells via the Cyclin D1-DILA1 axis and the PI3K/AKT/mTOR pathway downregulation  \nTaraneh Givi1, Fatemeh Mohajerani1, Zahra Moazezi Tehrankhah1, Mohammadjavad Karimi Taheri1, Maryam Amirahmadi2, Sadegh Babashah1, Majid Sadeghizadeh1*  \n1 Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran,  \n2 Food and Drug Laboratory Research Center, Food and Drug Administration, MOH MOE, Tehran, Iran  \n* [sadeghma@modares.ac.ir](sadeghma@modares.ac.ir)  \nAbstract  \nThis research investigates the effects of nano-curcumin on the expression of Cyclin D1 and DILA1 genes, as well as on the PI3K/AKT/mTOR pathway, in tamoxifensensitive and resistant MCF-7 breast cancer cell lines. The IC50 values were determined using the MTT assay. To establish tamoxifen-resistant MCF7 cells, a stepwise exposure to tamoxifen was conducted, gradually increasing the concentration to twice the IC50 dose. Following treatment with nano-curcumin, cell migration, proliferation, and apoptosis were evaluated using a wound healing assay and flow cytometry. Additionally, the impact of nano-curcumin on the PI3K/AKT/mTOR and Cyclin D1 signaling pathways was analyzed via qRT-PCR and Western blot. Nanocurcumin treatment significantly inhibits cell proliferation, viability, and migration and promotes apoptosis in tamoxifen-sensitive and resistant MCF7 cell lines. qRT-PCRand Western blot analyses revealed reduced expression of Cyclin D1, DILA1, NF-κB, PI3K, AKT, mTOR, VEGFα, MMP2 , and BCL2 , along with increased levels of PTEN, TIMP3, RECK, and BAX. Our results indicate that nano-curcumin mitigates drug resistance by decreasing DILA1 expression, which destabilizes Cyclin D1 protein and downregulates PI3K/AKT/mTOR pathway genes. Additionally, nano-curcumin induces apoptosis and inhibits migration. These findings suggest the nano-curcumin and tamoxifen combination may be a promising therapeutic strategy to overcome drug resistance in ER+ breast malignancies.  \nIntroduction  \nWorldwide, breast cancer affects one in every eight women, accounts for about 11.7 percent of all cancer cases, and is the second leading cause of cancer-related  \nPLOS One | [https://doi.org/10.1371/journal.pone.0335165](https://doi.org/10.1371/journal.pone.0335165) December 5, 2025 1 / 19  \nthe Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.  \nData availability statement: All data generated and analyzed during this study are original and are included in this article and its supplementary files.  \nFunding: This work is based upon research funded by Tarbiat Modares University Tarbiat Modares University as funders had no role in study design, data collection and analysis, decision to publish, or preparation of ","cbCaihXt6mud9Qws","https://ap.wps.com/l/cbCaihXt6mud9Qws","pdf",2983259,"English","# Abstract\n# Introduction\n# Materials and Methods\n# Results\n# Discussion\n# Conclusion","[{\"question\":\"How were tamoxifen-resistant MCF-7 cells generated in the study?\",\"answer\":\"Resistant MCF-7 cells were established by stepwise exposure to tamoxifen, gradually increasing the concentration to twice the IC50 dose.\"},{\"question\":\"Which assays were used to measure key cellular behaviors after nano-curcumin treatment?\",\"answer\":\"Cell migration, proliferation, and apoptosis were evaluated using a wound healing assay and flow cytometry.\"},{\"question\":\"What molecular changes did qRT-PCR and Western blot show after nano-curcumin treatment?\",\"answer\":\"Expression of Cyclin D1, DILA1, NF-κB, PI3K, AKT, mTOR, VEGFα, MMP2, and BCL2 decreased, while PTEN, TIMP3, RECK, and BAX increased.\"}]","Nano-curcumin enhances the sensitivity of tamoxifen-resistant breast cancer cells via the Cyclin D1-DILA1 axis and the PI3K/AKT/mTOR pathway downregulation | PDF",1790200622,48]