Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer
- 1Department of Oncology, Lombardi Comprehensive Cancer Center, Washington, DC 20057, USA
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.
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BibTeX
@misc{tam2026impact,
title = {{Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer}},
author = {S. Tam and S. Bahnassy and L. Jin and M. D. McCoy and S. Ranjit and R. Rahhal and A. T. McIntosh and D. K. Kung and G. Tang and S. M. Swain and R. B. Riggins},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.749891},
url = {https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Impact of Trastuzumab and Pertuzumab on HER2 Localization and the Estrogen Receptor Cistrome in ER+/HER2+ Breast Cancer
AU - S. Tam
AU - S. Bahnassy
AU - L. Jin
AU - M. D. McCoy
AU - S. Ranjit
AU - R. Rahhal
AU - A. T. McIntosh
AU - D. K. Kung
AU - G. Tang
AU - S. M. Swain
AU - R. B. Riggins
PY - 2026
DA - 2026/09/07
PB - bioRxiv
DO - 10.64898/2026.09.07.749891
UR - https://www.biorxiv.org/content/10.64898/2026.09.07.749891v1
AB - 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.
ER -