{
  "abstract": "Breast cancer (BC) remains a major global health concern, with rising incidence and mortality rates. Early diagnosis of BC plays an important role in its prevention. However, number of clinically validated biomarkers that enable accurate and minimally invasive diagnosis are still insufficient. Epigenetic modifications, particularly hypermethylation-mediated inactivation of numerous tumor suppressor genes occur early in tumorigenesis and are detectable even before the clinical onset, making them promising candidates for early diagnosis. Therefore, this study aimed to identify breast cancer-associated epigenetically regulated genes with potential diagnostic and biological relevance. A set of forty genes that displayed both hypermethylation and downregulation in BC were initially identified through bioinformatics analysis of publicly available datasets. Based on Gene Ontology (GO) and Reactome pathway enrichment analyses, eight genes were subsequently shortlisted for experimental analysis. Among these eight genes, LHX3 was significantly downregulated in both MCF-7 and MDA-MB-231 cells and in all tested BC tissue samples. LHX3 promoter hypermethylation was found in 80% of tumor tissues, compared to 32% in matched normal tissues. Aberrant LHX3 promoter methylation was significantly associated with metastasis status (P = 0.0002), with higher methylation in non-metastatic tumors, tumor size ≤20 mm (P = 0.002), and advanced tumor stage (P = 0.005). Given the complex pattern of these associations, findings were interpreted cautiously. Treatment with 5-aza-2’-deoxycytidine reversed promoter hypermethylation and restored LHX3 expression in MDA-MB-231 and MCF-7 cells. Additionally, ectopic expression of LHX3 not only reduced migration and proliferation but also induced cell death in BC cells. Our study provided the first evidence of epigenetically induced silencing of LHX3 and its anti-tumor role in BC. Furthermore, our findings support LHX3 as a candidate epigenetically regulated biomarker with tumor-suppressive properties in BC; however, independent cohort validation, quantitative methylation assays, and stage/subtype-stratified analyses are required before its diagnostic or prognostic utility can be established.",
  "abstract_shown": true,
  "affiliations": [
    "School of Biological Sciences, University of the Punjab, Lahore, Pakistan",
    "Shaukat Khanum Memorial Cancer Hospital & Research Centre, Lahore, Pakistan",
    "Faculty of Bioscience Engineering, Ghent University, Ghent, Belgium",
    "Forman Christian College, (A Chartered University), Lahore, Pakistan",
    "Department of Oral Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States of America",
    "Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Institute of Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom",
    "Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Kokab Farooq"
    },
    {
      "affs": [
        1
      ],
      "name": "Sheereen Gull"
    },
    {
      "affs": [
        2
      ],
      "name": "Zubia Farooq"
    },
    {
      "affs": [
        3
      ],
      "name": "Muhammad Talal Amin"
    },
    {
      "affs": [
        4
      ],
      "name": "Rana Salman Anjum"
    },
    {
      "affs": [
        5
      ],
      "name": "Muhammad Hassan Sarfraz"
    },
    {
      "affs": [
        6
      ],
      "name": "Ajaz Ahmad"
    },
    {
      "name": "Naveed Shahzad"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fmsk5wprvdrtw.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pone.0357378",
  "fulltext_url": null,
  "id": "fmsk5wprvdrtw",
  "issns": [
    "1932-6203"
  ],
  "landing_url": "https://doi.org/10.1371/journal.pone.0357378",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Epigenetics and DNA Methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Chromosome biology/Chromatin/Chromatin modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/DNA/DNA modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Epigenetics/Chromatin/Chromatin modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Epigenetics/DNA modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression/Chromatin/Chromatin modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression/DNA modification/DNA methylation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene types/Suppressor genes/Tumor suppressor genes"
    ],
    [
      "plos",
      "/Biology and life sciences/Molecular biology/Molecular biology techniques/Transfection"
    ],
    [
      "plos",
      "/Medicine and health sciences/Gastroenterology and hepatology/Liver diseases/Hepatocellular carcinoma"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Breast tumors/Breast cancer"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Carcinoma/Hepatocellular carcinoma"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Gastrointestinal tumors/Hepatocellular carcinoma"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Head and neck cancers"
    ],
    [
      "plos",
      "/Medicine and health sciences/Oncology/Cancers and neoplasms/Lung and intrathoracic tumors"
    ],
    [
      "plos",
      "/Research and analysis methods/Molecular biology techniques/Transfection"
    ]
  ],
  "openalex": "W7220855037",
  "pdf_url": "https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0357378&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-07",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/fmsk5wprvdrtw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pone.0357378",
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      "url": "https://doi.org/10.1371/journal.pone.0357378"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:gene expression",
      "subfield": "molecular-biology"
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    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
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    {
      "field": "medicine",
      "origin": "plos:cancers and neoplasms",
      "subfield": "oncology"
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  "title": "Integrative methylome and transcriptome analyses identify LHX3 as an epigenetically downregulated marker with tumor suppressive properties in breast cancer",
  "title_text": "Integrative methylome and transcriptome analyses identify LHX3 as an epigenetically downregulated marker with tumor suppressive properties in breast cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:30Z",
  "url": "https://research.draconitic.com/paper/fmsk5wprvdrtw",
  "venue": "PLOS One",
  "versions": []
}