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Background <p>Estrogen receptor–negative breast cancers are clinically heterogeneous. Two subtypes, Luminal Androgen Receptor and Molecular Apocrine Breast Cancers, are both defined by androgen signaling but identified through distinct transcriptomic classifiers. Their relationship remains unclear despite overlapping features.</p> Methods <p>We analyzed transcriptomic and genomic data from public and institutional cohorts using two classification systems. Gene set enrichment and immune deconvolution analyses were performed to characterize differences between overlapping and discordant tumors. A four-gene signature was developed and validated using RNA sequencing and RT-qPCR on both fresh-frozen and formalin-fixed samples.</p> Results <p>Substantial overlap was observed between the two subtypes, with shared activation of androgen and PI3K/AKT/mTOR signaling pathways. Discordant tumors were enriched in immune and stromal signals. A four-gene signature (<i>AR, FOXA1, SPDEF, TFF3</i>) identified overlapping tumors with high sensitivity and specificity across datasets and remained accurate in RT-qPCR assays on FFPE material.</p> Conclusion <p>Luminal Androgen Receptor and Molecular Apocrine Breast Cancers constitute a single molecular entity within estrogen receptor–negative breast cancers. The validated four-gene signature enables robust clinical identification and may guide future therapeutic stratification.</p>

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Molecular convergence of luminal androgen receptor and molecular apocrine defines a distinct entity in ER-negative breast tumors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月27日

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  • Adrien Borgel,
  • Etienne Camenen,
  • Catherine Miquel,
  • Philippe Bertheau,
  • Luis Teixeira,
  • Jacqueline Lehmann-Che

摘要

Background

Estrogen receptor–negative breast cancers are clinically heterogeneous. Two subtypes, Luminal Androgen Receptor and Molecular Apocrine Breast Cancers, are both defined by androgen signaling but identified through distinct transcriptomic classifiers. Their relationship remains unclear despite overlapping features.

Methods

We analyzed transcriptomic and genomic data from public and institutional cohorts using two classification systems. Gene set enrichment and immune deconvolution analyses were performed to characterize differences between overlapping and discordant tumors. A four-gene signature was developed and validated using RNA sequencing and RT-qPCR on both fresh-frozen and formalin-fixed samples.

Results

Substantial overlap was observed between the two subtypes, with shared activation of androgen and PI3K/AKT/mTOR signaling pathways. Discordant tumors were enriched in immune and stromal signals. A four-gene signature (AR, FOXA1, SPDEF, TFF3) identified overlapping tumors with high sensitivity and specificity across datasets and remained accurate in RT-qPCR assays on FFPE material.

Conclusion

Luminal Androgen Receptor and Molecular Apocrine Breast Cancers constitute a single molecular entity within estrogen receptor–negative breast cancers. The validated four-gene signature enables robust clinical identification and may guide future therapeutic stratification.