Journal
BRITISH JOURNAL OF CANCER
Volume 127, Issue 5, Pages 927-936Publisher
SPRINGERNATURE
DOI: 10.1038/s41416-022-01849-9
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Funding
- Breast Cancer Research Foundation (BCRF) Grant [BCRF-21-128]
- National Institute of General Medical Sciences (NIGMS) [T-32 GM113900, T32-GM007315, T32-GM007767]
- Ruth L. Kirschstein NRSA F31 award [F31CA254138]
- Rackham Predoctoral Fellowship Program
- Rackham Graduate School Research Grants
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The study investigated the radiosensitization effect of AR and ER inhibition in AR+/ER+ breast cancers. The results showed that AR inhibition does not modulate radiation sensitivity in AR+/ER+ breast cancer, while the efficacy of ER antagonists may depend on the expression of AR.
PURPOSE: Radiation therapy (RD 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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