{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:40:42Z","timestamp":1785429642888,"version":"3.56.0"},"reference-count":58,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sandler Program in Basic Science"},{"name":"NIH-NCI Physical Science Oncology Center","award":["U54CA143874"],"award-info":[{"award-number":["U54CA143874"]}]},{"name":"NIH","award":["P01AI091580"],"award-info":[{"award-number":["P01AI091580"]}]},{"name":"Gabrielle\u2019s Angel Foundation"},{"id":[{"id":"https:\/\/ror.org\/05pmyqf04","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008069","name":"UCSF","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008069","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Mark Foundation for Cancer Research Momentum Award"},{"id":[{"id":"https:\/\/ror.org\/00v7th354","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NCI","doi-asserted-by":"publisher","award":["R01 CA056721"],"award-info":[{"award-number":["R01 CA056721"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NCI","doi-asserted-by":"publisher","award":["K22 CA190511"],"award-info":[{"award-number":["K22 CA190511"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NCI","doi-asserted-by":"publisher","award":["R00 CA181490"],"award-info":[{"award-number":["R00 CA181490"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NCI","doi-asserted-by":"publisher","award":["1R01DK115728-01"],"award-info":[{"award-number":["1R01DK115728-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NCI","doi-asserted-by":"publisher","award":["NIH F31 CA200342"],"award-info":[{"award-number":["NIH F31 CA200342"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mammary gland development during puberty requires tightly coordinated epithelial proliferation, lineage specification, and branching morphogenesis, processes critically regulated by growth factor signaling. While epidermal growth factor receptor (EGFR) signaling is essential for ductal development, how its activity is quantitatively controlled within mammary epithelial cells (MECs) remains incompletely understood. Here, we identify Rasgrp1, a Ras guanine nucleotide exchange factor, as a key modulator of EGFR signaling in the mammary epithelium. Using Rasgrp1-deficient mice, primary MEC assays, and organoid models, we demonstrate that loss of Rasgrp1 leads to elevated EGFR\u2013Ras\u2013PI3K\u2013AKT and mTORC1-S6 signaling, resulting in enhanced proliferative capacity and aberrant EGF-driven branching. Transcriptomic analysis of organoids reveals that EGF signaling suppresses Wnt\/R-spondin-dependent stem-cell gene programs, suggesting that excessive EGFR activity disrupts stem cell maintenance. In vivo, Rasgrp1 deficiency causes impaired ductal elongation, persistent terminal end buds, and increased epithelial proliferation, indicating a breakdown in the spatial and temporal coordination of mammary morphogenesis. Together, our findings establish Rasgrp1 as a signaling rheostat that dampens EGFR pathway activity to support coordinated mammary gland development. These results highlight the importance of precise signaling calibration in epithelial development and suggest broader implications for Ras pathway regulation in tissue homeostasis and disease.<\/jats:p>","DOI":"10.3390\/cells15141288","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rasgrp1-Mediated Dampening of EGFR Signals Supports Coordinated Mammary Gland Development"],"prefix":"10.3390","volume":"15","author":[{"given":"Alexandr","family":"Samocha","sequence":"first","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8376-3385","authenticated-orcid":false,"given":"Lauren","family":"Shechtman","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunice Bonfil","family":"Tapia","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0781-611X","authenticated-orcid":false,"given":"Hanna M.","family":"Doh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5489-0067","authenticated-orcid":false,"given":"Oghenekevwe","family":"Gbenedio","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Sitarama","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7016-1155","authenticated-orcid":false,"given":"Quy H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua D.","family":"Rudolph","sequence":"additional","affiliation":[{"name":"UCSF Genomics CoLab, Lung Biology Center, School of Medicine, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter L.","family":"Eckalbar","sequence":"additional","affiliation":[{"name":"UCSF Genomics CoLab, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea J.","family":"Barczak","sequence":"additional","affiliation":[{"name":"UCSF Genomics CoLab, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Department of Structural Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Depeille","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. Christopher","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Physiology, Department of Structural Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon A.","family":"Lawson","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Kessenbrock","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4746-2811","authenticated-orcid":false,"given":"Jeroen P.","family":"Roose","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California San Francisco, 513 Parnassus Avenue, Room HSW-1325, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1186\/bcr1331","article-title":"Key stages in mammary gland development: The mammary end bud as a motile organ","volume":"7","author":"Hinck","year":"2005","journal-title":"Breast Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.semcdb.2014.04.019","article-title":"Cellular foundations of mammary tubulogenesis","volume":"31","author":"Huebner","year":"2014","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s10911-008-9084-6","article-title":"The ADAM17-amphiregulin-EGFR axis in mammary development and cancer","volume":"13","author":"Sternlicht","year":"2008","journal-title":"J. Mammary Gland Biol. Neoplasia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1126\/science.1067431","article-title":"Stromal effects on mammary gland development and breast cancer","volume":"296","author":"Wiseman","year":"2002","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1101\/gad.242511.114","article-title":"Mammary stem cells and the differentiation hierarchy: Current status and perspectives","volume":"28","author":"Visvader","year":"2014","journal-title":"Genes Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"a003186","DOI":"10.1101\/cshperspect.a003186","article-title":"Mammary gland growth factors: Roles in normal development and in cancer","volume":"2","author":"Hynes","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Samocha, A., Doh, H., Kessenbrock, K., and Roose, J.P. (2019). Unraveling Heterogeneity in Epithelial Cell Fates of the Mammary Gland and Breast Cancer. Cancers, 11.","DOI":"10.3390\/cancers11101423"},{"key":"ref_8","first-page":"777","article-title":"Activation and function of the epidermal growth factor receptor and erbB-2 during mammary gland morphogenesis","volume":"9","author":"Sebastian","year":"1998","journal-title":"Cell Growth Differ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1242\/dev.01966","article-title":"Mammary ductal morphogenesis requires paracrine activation of stromal EGFR via ADAM17-dependent shedding of epithelial amphiregulin","volume":"132","author":"Sternlicht","year":"2005","journal-title":"Development"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1242\/dev.126.2.335","article-title":"Signaling through the stromal epidermal growth factor receptor is necessary for mammary ductal development","volume":"126","author":"Wiesen","year":"1999","journal-title":"Development"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1038\/sj.onc.1208230","article-title":"Targeted disruption of ErbB2\/Neu in the mammary epithelium results in impaired ductal outgrowth","volume":"24","author":"Andrechek","year":"2005","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"17138","DOI":"10.1073\/pnas.0407057101","article-title":"ErbB2 is required for ductal morphogenesis of the mammary gland","volume":"101","author":"Bellinger","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R96","DOI":"10.1186\/bcr2198","article-title":"ErbB3 is required for ductal morphogenesis in the mouse mammary gland","volume":"10","author":"Bellinger","year":"2008","journal-title":"Breast Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8281","DOI":"10.1073\/pnas.1436402100","article-title":"Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality","volume":"100","author":"Tidcombe","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/nrc2960","article-title":"Ras superfamily GEFs and GAPs: Validated and tractable targets for cancer therapy?","volume":"10","author":"Vigil","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S0092-8674(03)00149-1","article-title":"Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS","volume":"112","author":"Margarit","year":"2003","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e00813","DOI":"10.7554\/eLife.00813","article-title":"Structural analysis of autoinhibition in the Ras-specific exchange factor RasGRP1","volume":"2","author":"Iwig","year":"2013","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e29002","DOI":"10.7554\/eLife.29002","article-title":"A Histidine pH sensor regulates activation of the Ras-specific guanine nucleotide exchange factor RasGRP1","volume":"6","author":"Vercoulen","year":"2017","journal-title":"eLife"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e01020","DOI":"10.7554\/eLife.01020","article-title":"Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies","volume":"2","author":"Daley","year":"2013","journal-title":"eLife"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cell.2008.11.051","article-title":"Digital signaling and hysteresis characterize ras activation in lymphoid cells","volume":"136","author":"Das","year":"2009","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jun, J.E., Rubio, I., and Roose, J.P. (2013). Regulation of Ras Exchange Factors and Cellular Localization of Ras Activation by Lipid Messengers in T Cells. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00239"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.1128\/MCB.01593-12","article-title":"Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS","volume":"33","author":"Jun","year":"2013","journal-title":"Mol. Cell. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.it.2013.02.004","article-title":"Ras and extracellular signal-regulated kinase signaling in thymocytes and T cells","volume":"34","author":"Kortum","year":"2013","journal-title":"Trends Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s11515-013-1276-9","article-title":"RasGRP Ras guanine nucleotide exchange factors in cancer","volume":"8","author":"Ksionda","year":"2013","journal-title":"Front. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1128\/MCB.01882-06","article-title":"Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes","volume":"27","author":"Roose","year":"2007","journal-title":"Mol. Cell. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10190","DOI":"10.1158\/0008-5472.CAN-07-2375","article-title":"RasGRP1 overexpression in the epidermis of transgenic mice contributes to tumor progression during multistage skin carcinogenesis","volume":"67","author":"Luke","year":"2007","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1093\/carcin\/bgu016","article-title":"Targeted deletion of RasGRP1 impairs skin tumorigenesis","volume":"35","author":"Sharma","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1038\/ncb3175","article-title":"RasGRP1 opposes proliferative EGFR-SOS1-Ras signals and restricts intestinal epithelial cell growth","volume":"17","author":"Depeille","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.ccell.2023.03.021","article-title":"Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression","volume":"41","author":"Jana","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1158\/0008-5472.CAN-12-1370","article-title":"CellMiner: A web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set","volume":"72","author":"Reinhold","year":"2012","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/79766","article-title":"RasGRP is essential for mouse thymocyte differentiation and TCR signaling","volume":"1","author":"Dower","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.cell.2006.09.048","article-title":"GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland","volume":"127","author":"Slorach","year":"2006","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e127552","DOI":"10.1172\/jci.insight.127552","article-title":"RasGRP1 is a potential biomarker to stratify anti-EGFR therapy response in colorectal cancer","volume":"5","author":"Gbenedio","year":"2019","journal-title":"JCI Insight"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1073\/pnas.1701464114","article-title":"Diverse regulation of mammary epithelial growth and branching morphogenesis through noncanonical Wnt signaling","volume":"114","author":"Kessenbrock","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1038\/nature04496","article-title":"Purification and unique properties of mammary epithelial stem cells","volume":"439","author":"Stingl","year":"2006","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/bcr2558","article-title":"Key signalling nodes in mammary gland development and cancer. Signalling downstream of PI3 kinase in mammary epithelium: A play in 3 Akts","volume":"12","author":"Wickenden","year":"2010","journal-title":"Breast Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/978-1-62703-125-7_14","article-title":"Three-dimensional cultures of mouse mammary epithelial cells","volume":"Volume 945","author":"Mroue","year":"2013","journal-title":"Methods in Molecular Biology"},{"key":"ref_40","first-page":"1065","article-title":"Derivation of a robust mouse mammary organoid system for studying tissue dynamics","volume":"144","author":"Jamieson","year":"2017","journal-title":"Development"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1016\/j.cell.2016.05.082","article-title":"Modeling Development and Disease with Organoids","volume":"165","author":"Clevers","year":"2016","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1234852","article-title":"Growing self-organizing mini-guts from a single intestinal stem cell: Mechanism and applications","volume":"340","author":"Sato","year":"2013","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature10337","article-title":"Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling","volume":"476","author":"Barker","year":"2011","journal-title":"Nature"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nature22306","article-title":"Surrogate Wnt agonists that phenocopy canonical Wnt and beta-catenin signalling","volume":"545","author":"Janda","year":"2017","journal-title":"Nature"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1016\/j.stem.2020.07.020","article-title":"Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo","volume":"27","author":"Miao","year":"2020","journal-title":"Cell Stem Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.cell.2017.11.010","article-title":"A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity","volume":"172","author":"Sachs","year":"2018","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"30350","DOI":"10.1074\/jbc.M103167200","article-title":"Cloning and characterization of three Xenopus slug promoters reveal direct regulation by Lef\/beta-catenin signaling","volume":"276","author":"Vallin","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16654","DOI":"10.1073\/pnas.1205822109","article-title":"Canonical Wnt signaling regulates Slug activity and links epithelial-mesenchymal transition with epigenetic Breast Cancer 1, Early Onset (BRCA1) repression","volume":"109","author":"Wu","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"33132","DOI":"10.1074\/jbc.M500608200","article-title":"Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression","volume":"280","author":"Gaur","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"15658","DOI":"10.1038\/srep15658","article-title":"Runx2 contributes to the regenerative potential of the mammary epithelium","volume":"5","author":"Ferrari","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1038\/nature10573","article-title":"Distinct stem cells contribute to mammary gland development and maintenance","volume":"479","author":"Rocha","year":"2011","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0092-8674(02)01014-0","article-title":"The beta-catenin\/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells","volume":"111","author":"Sancho","year":"2002","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Iglesias, J.M., Cairney, C.J., Ferrier, R.K., McDonald, L., Soady, K., Kendrick, H., Pringle, M.-A., O Morgan, R., Martin, F., and Smalley, M.J. (2015). Annexin A8 identifies a subpopulation of transiently quiescent c-kit positive luminal progenitor cells of the ductal mammary epithelium. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119718"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.devcel.2008.03.003","article-title":"Collective epithelial migration and cell rearrangements drive mammary branching morphogenesis","volume":"14","author":"Ewald","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1101\/gad.2025611","article-title":"Sustained activation of the HER1-ERK1\/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue","volume":"25","author":"Pasic","year":"2011","journal-title":"Genes Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1210\/mend.11.12.0019","article-title":"Targeted expression of a dominant negative epidermal growth factor receptor in the mammary gland of transgenic mice inhibits pubertal mammary duct development","volume":"11","author":"Xie","year":"1997","journal-title":"Mol. Endocrinol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1101\/gad.8.4.399","article-title":"The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase","volume":"8","author":"Luetteke","year":"1994","journal-title":"Genes Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1073\/pnas.92.5.1465","article-title":"A mutation in the epidermal growth factor receptor in waved-2 mice has a profound effect on receptor biochemistry that results in impaired lactation","volume":"92","author":"Fowler","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1288\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:20:00Z","timestamp":1784521200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,18]]},"references-count":58,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141288"],"URL":"https:\/\/doi.org\/10.3390\/cells15141288","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,18]]}}}