[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-331986-105":59,"doc-detail-331986-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","palb2-mutated-human-mammary-cells-display-a-broad-spectrum-of-morphological-and-functional-abnormalities-induced-by-increased-tgf-signaling","PALB2‑mutated human mammary cells display a broad spectrum of morphological and functional abnormalities induced by increased TGFβ signaling","","Heterozygous PALB2, BRCA1, and BRCA2 mutations contribute to high-risk hereditary breast cancer susceptibility, but how PALB2 loss alters cell behavior beyond DNA repair—especially in a three-dimensional context—remains unclear. Biologically relevant MCF10A mammary epithelial cell lines carrying clinically comparable PALB2 defects reveal spontaneous DNA damage, mitotic abnormalities, disturbed spheroid morphology, and increased migratory and invasive capacity, alongside broad transcriptome changes. Enhanced TGFβ signaling and KRT14 expression are functionally linked to partial restoration by inhibition and knockdown.",{"@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/palb2-mutated-human-mammary-cells-display-a-broad-spectrum-of-morphological-and-functional-abnormalities-induced-by-increased-tgf-signaling/331986/",{"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/palb2-mutated-human-mammary-cells-display-a-broad-spectrum-of-morphological-and-functional-abnormalities-induced-by-increased-tgf-signaling/331986.png","ImageObject",300,407,{"name":92,"@type":93},"Olivia Brown","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-22","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":34},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the central focus of this study on PALB2?","Question",{"text":112,"@type":113},"The study examines how PALB2 deficiency affects cell function beyond DNA repair, particularly in a three-dimensional cellular setting and during early malignancy steps.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were the experimental cell models generated?",{"text":117,"@type":113},"Human MCF10A mammary epithelial cells were modified using CRISPR/Cas9 gene editing to create bi- or monoallelically PALB2-mutated cell lines comparable to clinically important PALB2 defects.",{"name":119,"@type":110,"acceptedAnswer":120},"Which signaling pathway and marker are reported as enhanced in PALB2-mutated cells?",{"text":121,"@type":113},"TGFβ signaling and KRT14 expression are enhanced in PALB2-mutated cells, and their inhibition or knockdown leads to partial restoration of cell functions.","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},331986,1790406232,{"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":34,"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},16904993612988,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Cellular and Molecular Life Sciences (2024) 81:173  \n[https://doi.org/10.1007/s00018-024-05183-6](https://doi.org/10.1007/s00018-024-05183-6) Cellular and Molecular Life Sciences  \nPALB2‑mutated human mammary cells display a broad spectrum of morphological and functional abnormalities induced by increased TGFβ signaling  \nHanna Tuppurainen1 · Niina Laurila1 · Marjut Nätynki1 · Leila Eshraghi1,2 · Anna Tervasmäki1 · Louisa Erichsen3 · Claus Storgaard Sørensen3 · Katri Pylkäs1,4 · Robert Winqvist1 · Hellevi Peltoketo1  \nReceived: 2 June 2023 / Revised: 16 February 2024 / Accepted: 19 February 2024 © The Author(s) 2024  \nAbstract  \nHeterozygous mutations in any of three major genes, BRCA1, BRCA2 and PALB2, are associated with high-risk hereditary breast cancer susceptibility frequently seen as familial disease clustering. PALB2 is a key interaction partner and regulator of several vital cellular activities of BRCA1 and BRCA2, and is thus required for DNA damage repair and alleviation of replicative and oxidative stress. Little is however known about how PALB2-deficiency affects cell function beyond that, especially in the three-dimensional setting, and also about its role during early steps of malignancy development. To answer these questions, we have generated biologically relevant MCF10A mammary epithelial cell lines with mutations that are comparable to certain clinically important PALB2 defects. We show in a non-cancerous background how both mono-and biallelically PALB2-mutated cells exhibit gross spontaneous DNA damage and mitotic aberrations. Furthermore, PALB2-deficiency disturbs three-dimensional spheroid morphology, increases the migrational capacity and invasiveness of the cells, and broadly alters their transcriptome profiles. TGFβ signaling and KRT14 expression are enhanced in PALB2-mutated cells and their inhibition and knock down, respectively, lead to partial restoration of cell functions. KRT14-positive cells are also more abundant with DNA damage than KRT14-negative cells. The obtained results indicate comprehensive cellular changes upon PALB2 mutations, even in the presence of half dosage of wild type PALB2 and demonstrate how PALB2 mutations may predispose their carriers to malignancy.  \nKeywords Hereditary breast cancer susceptibility modeling · PALB2-edited cell lines · Three-dimensional cell growth and migration · Transcriptome profiling · TGFβ response · KRT14-positive cells  \nAbbreviations  \n\n| Hanna Tuppurainen and Niina Laurila contributed equally. |\n| --- |\n| Robert Winqvist and Hellevi Peltoketo shared senior authorship. |\n\n* Robert Winqvist [robert.winqvist@oulu.fi](robert.winqvist@oulu.fi)  \n* Hellevi Peltoketo [hellevi.peltoketo@oulu.fi](hellevi.peltoketo@oulu.fi)  \n1 Laboratory of Cancer Genetics and Tumor Biology, Translational Medicine Research Unit, Biocenter Oulu and Faculty of Medicine, Medical Research Center Oulu, University of Oulu, Oulu, Finland  \n2 Present Address: Garvan Institute of Medical Research, Sydney, Australia  \n3 Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark  \n4 Northern Finland Laboratory Centre, Oulu, Finland  \n3D  \nB–H  \nDDR  \nesiRNA  \nGFR-BME  \nHRD  \nHU  \nIPA  \nKD  \nNFκB  \nROS  \nSTRING  \nTGFβ  \nThree dimensional  \nBenjamini–Hochberg  \nDNA damage response  \nEndoribonuclease-prepared short interfering RNA  \nGrowth factor-reduced basement membrane extracts  \nHomologous recombination deficiency Hydroxy urea  \nIngenuity pathway analysis  \nKnock down  \nNuclear factor kappa B  \nReactive oxygen species  \nSearch tool for retrieval of interacting genes/ proteins  \nTransforming growth factor beta  \nTGFβR TGFβ receptor  \nTNFα Tumor necrosis factor alpha  \nIntroduction  \nPathogenic heritable gene variants are strongly involved in the etiology of breast carcinoma and estimated to cause as much as five to ten percent of this very common malignancy [1]. Based on its mutation frequency and disease penetrance, PALB2 is considered as the third ma","cbCaiaXED95ymwcd","https://ap.wps.com/l/cbCaiaXED95ymwcd","pdf",9115644,21,"English","# Abstract\n# Keywords\n# Introduction","[{\"question\":\"What is the central focus of this study on PALB2?\",\"answer\":\"The study examines how PALB2 deficiency affects cell function beyond DNA repair, particularly in a three-dimensional cellular setting and during early malignancy steps.\"},{\"question\":\"How were the experimental cell models generated?\",\"answer\":\"Human MCF10A mammary epithelial cells were modified using CRISPR/Cas9 gene editing to create bi- or monoallelically PALB2-mutated cell lines comparable to clinically important PALB2 defects.\"},{\"question\":\"Which signaling pathway and marker are reported as enhanced in PALB2-mutated cells?\",\"answer\":\"TGFβ signaling and KRT14 expression are enhanced in PALB2-mutated cells, and their inhibition or knockdown leads to partial restoration of cell functions.\"}]","PALB2‑mutated human mammary cells display a broad spectrum of morphological and functional abnormalities induced by increased TGFβ signaling | PDF",1789996169,53]