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Using cellular fractionation, immunofluorescence, chromatin immunoprecipitation, and genome-wide profiling (CUT&amp;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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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 (\n                    <jats:italic>FZD8<\/jats:italic>\n                    ,\n                    <jats:italic>RELA<\/jats:italic>\n                    ). 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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.07.749891","type":"posted-content","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:15:17Z","timestamp":1789067717000},"source":"Crossref","is-referenced-by-count":0,"title":["Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+\/HER2+ Breast Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-436X","authenticated-orcid":false,"given":"Stanley","family":"Tam","sequence":"first","affiliation":[{"name":"Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20057, 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