{
  "abstract": "Invasive lobular carcinoma (ILC) is a common subtype of breast cancer, molecularly defined by genetic loss of CDH1, and subsequent loss of cell adhesion protein E-cadherin, in ~95% of ILC. Though CDH1 loss occurs early in ILC oncogenesis, it is unclear how this facilitates transformation. We modeled early CDH1 loss using “normal” human mammary epithelial cells (HMEC), i.e., finite lifespan cells reflecting early hyperplasia, and targeted E-cadherin signaling using antibodies versus causing genetic CDH1 loss using siRNA or CRISPR/Cas9-knockout. Transcriptome analysis across four HMEC models showed that the mode of E-cadherin targeting is critical for the subsequent phenotype. Antibody-mediated inhibition of cell-cell contacts induced gene signatures of epithelial-mesenchymal transition (EMT), consistent with the role of E-cadherin suppression during the EMT process. Conversely, genetic CDH1 loss – as in ILC oncogenesis – repressed EMT signatures, and instead remodeled gene expression toward a luminal epithelial phenotype. RNA-seq, single cell transcriptomics, flow cytometry, microscopy, and ATAC-seq analyses support that CDH1 loss induces lineage remodeling to a luminal state, which is mirrored in transcriptomic analysis of clinical ILC precursor lesions. By isolating luminal versus basal cells prior to CDH1 knockout, we found that CDH1 loss led to remodeling of lineage identity in both populations, converging on a new lineage homeostasis with a luminal progenitor-like phenotype. Consistent with the shift to a luminal progenitor phenotype, CDH1 loss enhanced proliferative capacity over the finite lifespan of the HMECs, highlighting a feature of early CDH1 loss that may contribute to clonal advantage during tumor initiation. Moreover, CDH1 loss enhanced anoikis resistance, a defining feature of ILC cells. Our findings support that genetic loss of CDH1 in mammary epithelial cells induces transcriptional and phenotypic changes consistent with lineage identity remodeling toward a luminal progenitor-like state, which may underpin the mechanism by which early CDH1 loss mediates ILC oncogenesis. Author summary: Invasive lobular carcinoma (ILC) is a unique form of breast cancer that accounts for approximately 15 percent of all breast cancer diagnoses. A key molecular hallmark of ILC is the genetic loss of the gene encoding E-cadherin, CDH1. Though CDH1 loss is one of the earliest events in ILC oncogenesis, it remains poorly understood how CDH1 loss permits transformation from normal mammary cells to ILC. To address this gap, we developed cell culture models of early CDH1 loss using “normal” human mammary epithelial cells (HMEC), i.e., non-transformed mammary cells from healthy reduction mammoplasties reflecting early hyperplasia, and assessed cellular phenotypes upon CDH1 loss. We identified that the genetic loss of CDH1, as opposed to blocking E-cadherin protein, remodeled cellular gene expression and drove a reprogramming of cell lineage identity, with cells adopting a progenitor-like phenotype upon CDH1 loss and acquiring ILC-like phenotypes. These data provide new mechanistic insight into how loss of CDH1 is a key oncogenic event in ILC, and may explain distinct aspects of the clinical presentation of ILC among breast cancers.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathology, University of Colorado Anschutz, Aurora, Colorado, United States of America",
    "Department of Pharmacology, Molecular Pharmacology and Therapeutics (MPaT) Program, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America",
    "University of Colorado Cancer Center, University of Colorado Anschutz, Aurora, Colorado, United States of America",
    "Department of Biomedical Informatics, University of Colorado Anschutz, Aurora, Colorado, United States of America",
    "Hennepin County Medical Center, Minneapolis, Minnesota, United States of America",
    "Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America",
    "Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota, United States of America"
  ],
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    {
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        0
      ],
      "name": "Maggie Musick",
      "orcid": "0000-0002-3564-2527"
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    {
      "affs": [
        1
      ],
      "name": "Chinasa A. Ufondu",
      "orcid": "0009-0007-3883-2936"
    },
    {
      "affs": [
        0
      ],
      "name": "Carmen E. Rowland"
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    {
      "affs": [
        0
      ],
      "name": "Micaela E. Brown"
    },
    {
      "affs": [
        0
      ],
      "name": "Joseph L. Sottnik",
      "orcid": "0000-0002-0263-3608"
    },
    {
      "affs": [
        0
      ],
      "name": "Madeleine T. Shackleford"
    },
    {
      "affs": [
        0
      ],
      "name": "Camryn S. Nesiba"
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    {
      "affs": [
        2,
        3
      ],
      "name": "Etienne P. Danis",
      "orcid": "0000-0002-5651-8111"
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    {
      "affs": [
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        3
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      "name": "Andrew E. Goodspeed"
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    {
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        4
      ],
      "name": "Richard Zera"
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    {
      "affs": [
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      ],
      "name": "Arthur T. Johnson"
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    {
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        6
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      "name": "Kathryn L. Schwertfeger"
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    {
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      ],
      "name": "Andrew C. Nelson",
      "orcid": "0000-0002-4741-0010"
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    {
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        6
      ],
      "name": "Julie H. Ostrander",
      "orcid": "0000-0002-5038-6875"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Matthew J. Sikora",
      "orcid": "0000-0003-2915-7442"
    }
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  "doi": "10.1371/journal.pgen.1012351",
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  "published": "2026-10-27",
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  "subjects": [
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      "field": "biology",
      "origin": "plos:cell biology",
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  "title": "CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells",
  "title_text": "CDH1 loss remodels gene expression and lineage identity in human mammary epithelial cells",
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