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Accordingly, there is a need for novel animal models to understand its pathogenesis and plasticity. Since alterations in\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    and\n                    <jats:italic>TP53<\/jats:italic>\n                    genes are common in metaplastic breast cancer, we generated a mouse model of metaplastic breast cancer by driving\n                    <jats:italic>Pik3ca<\/jats:italic>\n                    activation and\n                    <jats:italic>Trp53<\/jats:italic>\n                    loss in keratin 15\u2010expressing mammary cells. In this model, male and female mice developed spontaneous mammary lesions, with malignancy reliant on loss of both\n                    <jats:italic>Trp53<\/jats:italic>\n                    alleles. Importantly, tumors of this model are heterogeneous and resemble the mixed histology of metaplastic breast cancer by exhibiting squamous cell carcinoma, carcinosarcoma, and sarcoma features. We developed mammary cell lines from mouse tumors representing these different histological subtypes. These\n                    <jats:italic>Pik3ca<\/jats:italic>\n                    \u2010activated tumor cells were more sensitive to alpelisib, a p110\u03b1\u2010selective inhibitor approved by the FDA for the treatment of some\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    mutant cancers, compared to\n                    <jats:italic>Pik3ca<\/jats:italic>\n                    WT cells. Additionally, some of these cell lines expressed the androgen receptor, a hormone receptor targeted in prostate cancer and currently under investigation as a therapeutic target in breast cancer. Transplantation of these cell lines into recipient mice maintained histological heterogeneity. Additionally, transplantation of either Epcam+ or Epcam\u2212 sorted cells, representing epithelial cell\u2010like and nonepithelial cell\u2010like, respectively, from a carcinosarcoma cell line, initiated tumor formation. Both sorted populations formed tumors with mixed histologic features, demonstrating plasticity arising from different tumor\u2010initiating components. These new models of metaplastic breast cancer from relevant genetic drivers serve as a platform for identifying mechanisms driving plasticity that could inform therapeutic strategies based on histology and reveal how plasticity alters treatment efficacy. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6463","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T04:16:27Z","timestamp":1755144987000},"page":"213-224","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activation of\n                    <scp>PI3K<\/scp>\n                    and deletion of p53 in keratin 15\u2010expressing mouse mammary cells induces tumor heterogeneity and plasticity modeling metaplastic breast cancer"],"prefix":"10.1002","volume":"267","author":[{"given":"Khoa A","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren E","family":"McLemore","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Ke","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"},{"name":"Department of Pathology &amp; Laboratory Medicine University of California Davis  Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa N","family":"DePledge","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynelle P","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D","family":"Aleman","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Debretsion","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Laboratory Medicine University of California Davis  Sacramento CA USA"},{"name":"VA Northern California Health Care System  Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9846-488X","authenticated-orcid":false,"given":"Christian D","family":"Young","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado Anschutz Medical Campus  Aurora CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11412"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14129"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26213-y"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-1969-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01785-9"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1075"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11404"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature21386"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0262-1"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.4137\/CPath.S31563"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-023-00511-6"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-020-01353-z"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0224726"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-3441"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-2857"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2014-0200-OA"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2018.11.023"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-011-1686-9"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000002341"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15283-z"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-019-0208-x"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt950"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.08.041"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.8.994"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21186585"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/mc.21896"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1354\/vp.43-1-36"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-015-0539-6"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0560.1999.tb01814.x"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007110"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-024-00697-5"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.71.3495"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813904"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3652"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0738"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4579"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14669"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14665"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910370103"},{"key":"e_1_2_8_41_1","volume-title":"Treasure Island (FL) Ineligible Companies. 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