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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月24日

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  • Breanna McBean,
  • Benjamin Hauk,
  • Anna R. Michmerhuizen,
  • Benjamin C. Chandler,
  • Andrea M. Pesch,
  • Lynn M. Lerner,
  • Douglas Gurdak,
  • Connor Ward,
  • Priyanka Rana,
  • Reine Abou Zeidane,
  • Vesna Mercer,
  • Mingfang Tao,
  • Ethan Hochmuth,
  • Kassidy M. Jungles,
  • Stephanie The,
  • Meilan Liu,
  • Daniel E. Spratt,
  • Alan P. Boyle,
  • Lori J. Pierce,
  • Corey W. Speers

摘要

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.