ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers

Sep 21, 2026

Background: HOXB13/IL17RB gene expression biomarkers predict response to adjuvant and extended endocrine therapy in early-stage ER+ HER2-breast tumors, yet HOXB13 expression in HER2+ and ER− cancers remains limited. Methods: Expression, genomic copy number, mutational signatures, and clinical outcomes were analyzed in TGGA and METABRIC cohorts and validated using tri-colored fluorescence in situ hybridization. Results: HOXB13 was higher in HER2+ and ER− groups; ERBB2/HOXB13 co-amp with interstitial BRCA1 loss showed distinctive mutational and copy-number patterns and shorter progression-free survival.

LanguageEnglish

CategoryResearch & Report

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Abstract

Background

Methods

Results

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Background

Mitsiades etal. Breast Cancer Research (2024) 26:185 Breast Cancer Research [https://doi.org/10.1186/s13058-024-01943-1](https://doi.org/10.1186/s13058-024-01943-1) RESEARCH Open Access ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers Irene Rin Mitsiades 1, Maristela Onozato5, A. John Iafrate 1,3,4, Daniel Hicks 1,3,4,6, Doğa C. Gülhan 1,2,4, Dennis C. Sgroi 1,3,4*† and Esther Rheinbay 1,2,4*† Abstract Background The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2-breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data on HOXB13 expression in HER2+ and ER-breast cancers. Herein, we studied the expression of HOXB13 in large cohorts of HER2+ and ER-breast cancers. Methods We investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescence in situ hybridization. Results In the TCGA breast cancer cohort, HOXB13 gene expression was significantly higher in HER2+ versus HER2-breast cancers, and its expression was also significantly higher in the ER-versus ER+ breast cancers. HOXB13 is frequently co-gained or co-amplified with ERBB2 . Joint copy gains of HOXB13 and ERBB2 occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial loss that includes the tumor suppressor BRCA1 . ERBB2/HOXB13 co-amp tumors with interstitial BRCA1 loss exhibit a mutational signature associated with APOBEC deaminase activity and copy number signatures associated with chromothripsis and genomic instability. Among ERBB2-amplified tumors of different tissue origins, ERBB2/HOXB13 co-amp with a BRCA1 loss appeared to be enriched in breast cancer compared to other tumor types. Lastly, patients with ERBB2/HOXB13 co-amplified and BRCA1 lost tumors displayed a significantly shorter progression-free survival (PFS) than those with ERBB2-only amplifications. The difference in PFS was restricted to the ER-subset patients and this difference in PFS was not solely driven by HOXB13 gene expression. †Dennis C. Sgroi and Esther Rheinbay contributed equally to this work. *Correspondence: Dennis C. Sgroi[dsgroi@mgh.harvard.edu](dsgroi@mgh.harvard.edu)[ ](dsgroi@mgh.harvard.edu)Esther Rheinbay[erheinbay@mgh.harvard.edu](erheinbay@mgh.harvard.edu) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/l](vecommons.org/l)icenses/by-nc-nd/4.0/. Mitsiades et al. Breast Cancer Research (2024) 26:185 Page 2 of 15 Conclusions HOXB13 is frequently co-gained with ERBB2 at both low-copy number level

FAQs

What is the study’s central question about HOXB13 expression?

The study addresses how HOXB13 expression is distributed across HER2+ and ER− breast cancers, where data have been limited compared with ER+ disease.

How did the researchers validate genomic amplification findings?

Genomic amplification data were validated using tri-colored fluorescence in situ hybridization.

What clinical impact was associated with ERBB2/HOXB13 co-amplified tumors with interstitial BRCA1 loss?

Patients with these tumors showed significantly shorter progression-free survival, with the difference primarily confined to the ER-subset.

Sep 21, 2026

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