Androgen and oestrogen receptor co-expression determines the efficacy of hormone receptor-mediated radiosensitisation in breast cancer

  • Br J Cancer. 2022 Sep;127(5):927-936. doi: 10.1038/s41416-022-01849-9.
Anna R Michmerhuizen  1  2  3 ,  Lynn M Lerner  1 ,  Connor Ward  1 ,  Andrea M Pesch  1  2  4 ,  Amanda Zhang  1 ,  Rachel Schwartz  1 ,  Kari Wilder-Romans  1 ,  Joel R Eisner  5 ,  James M Rae  2  4  6 ,  Lori J Pierce  1  2 ,  Corey W Speers  7  8
Affiliations
  • 1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
  • 2. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 3. Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI, USA.
  • 4. Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
  • 5. Innocrin Pharmaceuticals, Durham, NC, USA.
  • 6. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 7. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 8. Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
PMID: 35618789 DOI: 10.1038/s41416-022-01849-9
Abstract

Purpose: Radiation therapy (RT) and hormone receptor (HR) inhibition are used for the treatment of HR-positive breast cancers; however, little is known about the interaction of the Androgen Receptor (AR) and Estrogen receptor (ER) in response to RT in AR-positive, ER-positive (AR+/ER+) breast cancers. Here we assessed radiosensitisation of AR+/ER+ cell lines using pharmacologic or genetic inhibition/degradation of AR and/or ER.

Methods: Radiosensitisation was assessed with AR antagonists (enzalutamide, apalutamide, darolutamide, seviteronel, ARD-61), ER antagonists (tamoxifen, fulvestrant) or using knockout of AR.

Results: Treatment with AR antagonists or ER antagonists in combination with RT did not result in radiosensitisation changes (radiation enhancement ratios [rER]: 0.76-1.21). Fulvestrant treatment provided significant radiosensitisation of CAMA-1 and BT-474 cells (rER: 1.06-2.0) but not ZR-75-1 cells (rER: 0.9-1.11). Combining tamoxifen with enzalutamide did not alter radiosensitivity using a 1 h or 1-week pretreatment (rER: 0.95-1.14). Radiosensitivity was unchanged in AR knockout compared to Cas9 cells (rER: 1.07 ± 0.11), and no additional radiosensitisation was achieved with tamoxifen or fulvestrant compared to Cas9 cells (rER: 0.84-1.19).

Conclusion: While radiosensitising in AR + TNBC, AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast Cancer. The efficacy of ER antagonists in combination with RT may also be dependent on AR expression.

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