ER⁻/PR⁺ breast cancer: from diagnostic discordance to precision therapy.
- 1Department of Thyroid and Breast Surgery, Union Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan, China.
- 2Department of Orthopedics, Union Hospital,Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- 3Department of Thyroid and Breast Surgery, People's Hospital of Dongxihu District Wuhan City and Union Dongxihu Hospital, Huazhong University of Science and Technology, Wuhan, China.
Abstract
Estrogen receptor-negative/progesterone receptor-positive/human epidermal growth factor receptor 2-negative (ER⁻/PR⁺/HER2⁻)breast cancer is a rare, controversial type that makes up about 0. 3% of all breast cancer cases and does not follow the traditional ER→PR regulatory hierarchy. This review synthesizes the available evidence on the diagnostic evaluation, clinicopathological characteristics, molecular mechanisms, prognosis, and treatment of ER⁻/PR⁺/HER2⁻(ER⁻/PR⁺) breast cancer. Although there are false-negative ER staining results and pre-analytical/analytical factors, a number of clinical and transcriptomic data support the existence of a reproducible ER⁻/PR⁺subgroup with molecular heterogeneity. These tumors often have a high histological grade, elevated Ki-67 expression, TP53 alterations, and basal-like features, and are closer to triple-negative breast cancer than luminal disease. Potential drivers include ER-independent non-canonical PR activation, epigenetic dysregulation, kinase-mediated receptor phosphorylation, membrane-associated progesterone signaling and receptor network reprogramming. Direct subtype-specific evidence remains limited, and the effectiveness of conventional endocrine therapy is unknown. Current guidelines classify these tumors as hormone receptor-positive/HER2-negative, obscuring clinically relevant heterogeneity. Standardized repeat testing and multi-omic characterization are thus required. Future studies should prioritize prospective multicenter cohorts with paired pre-treatment and post-treatment receptor testing, spatial or single-cell characterization, biomarker-guided stratification and adaptive clinical trials. A PR-oriented precision-medicine framework may improve diagnostic classification and help identify therapeutic vulnerabilities in biologically distinct patient subsets. In addition, this rare phenotype may serve as a useful model for investigating lineage plasticity and endocrine resistance.
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BibTeX
@article{shao2026erpr,
title = {{ER⁻/PR⁺ breast cancer: from diagnostic discordance to precision therapy.}},
author = {Yuanhao Shao and Meng Zhou and Zhenwei Hu and Bin Wu and Jing Zhou},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1961666},
url = {https://europepmc.org/article/MED/42898714},
note = {CC BY},
}
RIS
TY - JOUR
TI - ER⁻/PR⁺ breast cancer: from diagnostic discordance to precision therapy.
AU - Yuanhao Shao
AU - Meng Zhou
AU - Zhenwei Hu
AU - Bin Wu
AU - Jing Zhou
PY - 2026
DA - 2026/10/05
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1961666
UR - https://europepmc.org/article/MED/42898714
AB - Estrogen receptor-negative/progesterone receptor-positive/human epidermal growth factor receptor 2-negative (ER⁻/PR⁺/HER2⁻)breast cancer is a rare, controversial type that makes up about 0. 3% of all breast cancer cases and does not follow the traditional ER→PR regulatory hierarchy. This review synthesizes the available evidence on the diagnostic evaluation, clinicopathological characteristics, molecular mechanisms, prognosis, and treatment of ER⁻/PR⁺/HER2⁻(ER⁻/PR⁺) breast cancer. Although there are false-negative ER staining results and pre-analytical/analytical factors, a number of clinical and transcriptomic data support the existence of a reproducible ER⁻/PR⁺subgroup with molecular heterogeneity. These tumors often have a high histological grade, elevated Ki-67 expression, TP53 alterations, and basal-like features, and are closer to triple-negative breast cancer than luminal disease. Potential drivers include ER-independent non-canonical PR activation, epigenetic dysregulation, kinase-mediated receptor phosphorylation, membrane-associated progesterone signaling and receptor network reprogramming. Direct subtype-specific evidence remains limited, and the effectiveness of conventional endocrine therapy is unknown. Current guidelines classify these tumors as hormone receptor-positive/HER2-negative, obscuring clinically relevant heterogeneity. Standardized repeat testing and multi-omic characterization are thus required. Future studies should prioritize prospective multicenter cohorts with paired pre-treatment and post-treatment receptor testing, spatial or single-cell characterization, biomarker-guided stratification and adaptive clinical trials. A PR-oriented precision-medicine framework may improve diagnostic classification and help identify therapeutic vulnerabilities in biologically distinct patient subsets. In addition, this rare phenotype may serve as a useful model for investigating lineage plasticity and endocrine resistance.
SN - 2234-943X
ER -