2. Academic Validation
  3. Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models

Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models

  • NPJ Breast Cancer. 2022 Mar 10;8(1):31. doi: 10.1038/s41523-022-00397-y.
Anna R Michmerhuizen 1 2 3,  Lynn M Lerner 1,  Andrea M Pesch 1 2 4,  Connor Ward 1,  Rachel Schwartz 1,  Kari Wilder-Romans 1,  Meilan Liu 1,  Charles Nino 1 2 3,  Kassidy Jungles 1 2 4,  Ruth Azaria 3,  Alexa Jelley 1,  Nicole Zambrana Garcia 2,  Alexis Harold 1 2,  Amanda Zhang 1,  Bryan Wharram 1,  Daniel F Hayes 2 5,  James M Rae 2 4 5,  Lori J Pierce 1 2,  Corey W Speers 6 7
Affiliations

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 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA. [email protected].
  • 7 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. [email protected].
PMID: 35273179 DOI: 10.1038/s41523-022-00397-y
Abstract

Endocrine therapy (ET) is an effective first-line therapy for women with estrogen receptor-positive (ER + ) breast cancers. While both ionizing radiation (RT) and ET are used for the treatment of women with ER+ breast Cancer, the most effective sequencing of therapy and the effect of ET on tumor radiosensitization remains unclear. Here we sought to understand the effects of inhibiting Estrogen Receptor (ER) signaling in combination with RT in multiple preclinical ER+ breast Cancer models. Clonogenic survival assays were performed using variable pre- and post-treatment conditions to assess radiosensitization with estradiol, estrogen deprivation, tamoxifen, fulvestrant, or AZD9496 in ER+ breast Cancer cell lines. Estrogen stimulation was radioprotective (radiation enhancement ratios [rER]: 0.51-0.82). Conversely, when given one hour prior to RT, ER inhibition or estrogen depletion radiosensitized ER+ MCF-7 and T47D cells (tamoxifen rER: 1.50-1.60, fulvestrant rER: 1.76-2.81, AZD9496 rER: 1.33-1.48, estrogen depletion rER: 1.47-1.51). Combination treatment resulted in an increase in double-strand DNA (dsDNA) breaks as a result of inhibition of non-homologous end joining-mediated dsDNA break repair with no effect on homologous recombination. Treatment with tamoxifen or fulvestrant in combination with RT also increased the number of senescent cells but did not affect Apoptosis or cell cycle distribution. Using an MCF-7 xenograft model, concurrent treatment with tamoxifen and RT was synergistic and resulted in a significant decrease in tumor volume and a delay in time to tumor doubling without significant toxicity. These findings provide preclinical evidence that concurrent treatment with ET and RT may be an effective radiosensitization strategy.

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