{
  "abstract": "Background: Although anti-HER2 monoclonal antibody therapy with trastuzumab and pertuzumab is highly effective for HER2-positive breast cancer, co-expression of estrogen receptor (ER) significantly reduces pathologic complete response rates. Objective: We investigated how HER2-targeted inhibition affects HER2 cellular localization and ER genomic binding in ER-positive, HER2-positive breast cancer. Methods: We evaluated HER2 localization in a tissue microarray of treatment-naive patients. Using cellular fractionation, immunofluorescence, chromatin immunoprecipitation, and genome-wide profiling (CUT&RUN), we evaluated HER2 localization and ER genomic binding following acute anti-HER2 treatment and in models of treatment resistance. The treatment-induced ER-bound gene signature was assessed for associations with pathologic complete response and survival in breast cancer clinical cohorts. Results: In treatment-naive primary breast tumors, nuclear HER2 inversely correlated with ER levels. In cell models, treatment with trastuzumab and pertuzumab induced nuclear and chromatin accumulation of HER2. Concurrently, acute anti-HER2 treatment displaced ER from canonical estrogen response elements at classical target genes, yet genome-wide profiling revealed redistribution of ER binding toward non-canonical zinc finger motifs adjacent to pro-survival Wnt and RAGE pathway genes (FZD8, RELA). Expression of a drug-induced ER-bound gene signature was significantly higher in tumors of individuals who did not achieve pathologic complete response following neoadjuvant anti-HER2 therapy and significantly correlated with reduced distant metastasis-free survival in clinical cohorts. Conclusions: Anti-HER2 targeted therapy causes dynamic cistromic reprogramming of ER from classical estrogen pathways toward alternative pro-survival networks. These findings implicate ER redistribution as a possible mediator of resistance and highlight novel therapeutic targets in ER-positive, HER2-positive breast cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "S. Tam"
    },
    {
      "name": "S. Bahnassy"
    },
    {
      "name": "L. Jin"
    },
    {
      "name": "M. D. McCoy"
    },
    {
      "name": "S. Ranjit"
    },
    {
      "name": "R. Rahhal"
    },
    {
      "name": "A. T. McIntosh"
    },
    {
      "name": "D. K. Kung"
    },
    {
      "name": "G. Tang"
    },
    {
      "name": "S. M. Swain"
    },
    {
      "affs": [
        0
      ],
      "name": "R. B. Riggins"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3fhea46x9pm62.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.07.749891",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1.full",
  "id": "3fhea46x9pm62",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2730|HER2/EGFR in Cancer Research"
    ]
  ],
  "openalex": "W7212132206",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-07",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3fhea46x9pm62.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:58Z",
      "native_id": "10.64898/2026.09.07.749891",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer",
  "title_text": "Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:58Z",
  "url": "https://research.draconitic.com/paper/3fhea46x9pm62",
  "venue": "bioRxiv",
  "versions": []
}