Transcriptomic analysis to uncover the mechanism of radiosensitization of AR-positive triple-negative breast cancers with AR inhibition

  • NPJ Breast Cancer. 2026 Feb 24;12(1):50. doi: 10.1038/s41523-026-00916-1.
Breanna McBean  #  1  2  3 ,  Benjamin Hauk  #  4 ,  Anna R Michmerhuizen  #  1 ,  Benjamin C Chandler  1 ,  Andrea M Pesch  1 ,  Lynn M Lerner  1 ,  Douglas Gurdak  4  5 ,  Connor Ward  1 ,  Priyanka Rana  4  5 ,  Reine Abou Zeidane  4  5 ,  Vesna Mercer  4  5 ,  Mingfang Tao  4  5 ,  Ethan Hochmuth  4  5 ,  Kassidy M Jungles  1 ,  Stephanie The  1 ,  Meilan Liu  1 ,  Daniel E Spratt  4  5 ,  Alan P Boyle  2  3 ,  Lori J Pierce  1 ,  Corey W Speers  6  7  8
Affiliations
  • 1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • 2. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
  • 3. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • 4. University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA.
  • 5. Case Comprehensive Cancer Center, Cleveland, OH, USA.
  • 6. University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA. [email protected].
  • 7. Case Comprehensive Cancer Center, Cleveland, OH, USA. [email protected].
  • 8. Department of Radiation Oncology, University of Alabama, Birmingham, Birmingham, AL, UK. [email protected].
  • # Contributed equally.
PMID: 41735341 DOI: 10.1038/s41523-026-00916-1
Abstract

The Androgen Receptor (AR) has been identified as a driver of tumor growth and radioresistance in triple-negative breast cancers (TNBC), though the mechanistic role of AR in response to radiation therapy (RT) remains unknown. Here, we demonstrate that inhibition with the second-generation anti-androgen, apalutamide, but not darolutamide, is sufficient to radiosensitize AR+ TNBC models (rER: 1.34-1.41; rER: 0.96-1.11, respectively). Cells with low AR expression were not radiosensitized by AR inhibition (rER: 0.96-1.03). Mechanistically, while stimulation with the AR-agonist R1881 is sufficient to induce nuclear translocation of AR in AR+ TNBC cells, AR inhibition with enzalutamide, apalutamide, or darolutamide blocked AR nuclear translocation. When cells are treated with R1881+RT, nuclear translocation of AR was induced at similar or greater levels compared to R1881 alone in AR+ TNBC cells. Combination treatment of RT with enzalutamide reduced nuclear localization of AR (32-39% reduction) compared to RT alone. Transcriptional evaluation with RNA-Seq after AR stimulation and RT demonstrated changes in the MAPK/ERK signaling pathway, among Others. Overexpression of ERK reduces the radiosensitizing ability of second-generation anti-androgens, suggesting that AR-mediated radioresistance may be due, at least in part, to downstream MAPK/ERK signaling. These findings suggest that AR-mediated radioresistance is at least partially due to downstream MAPK/ERK signaling. Together this work builds on the mechanistic understanding of AR-mediated radioresistance in AR+ TNBC which may expose vulnerabilities in resistance to combination treatment with AR inhibition and RT.

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