Estrogen receptor inhibition mediates radiosensitization of ER-positive breast cancer models.
Journal
NPJ breast cancer
ISSN: 2374-4677
Titre abrégé: NPJ Breast Cancer
Pays: United States
ID NLM: 101674891
Informations de publication
Date de publication:
10 Mar 2022
10 Mar 2022
Historique:
received:
27
09
2021
accepted:
03
02
2022
entrez:
11
3
2022
pubmed:
12
3
2022
medline:
12
3
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35273179
doi: 10.1038/s41523-022-00397-y
pii: 10.1038/s41523-022-00397-y
pmc: PMC8913671
doi:
Types de publication
Journal Article
Langues
eng
Pagination
31Subventions
Organisme : NCI NIH HHS
ID : R21 CA267147
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007767
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : T32-GM007315
Organisme : NIGMS NIH HHS
ID : T32 GM113900
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007863
Pays : United States
Organisme : Breast Cancer Research Foundation (BCRF)
ID : BCRF-21-128
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : T32-GM007863
Organisme : NIGMS NIH HHS
ID : T32 GM007315
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : T32-GM113900
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : F31CA254138
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : T32-GM007767
Organisme : NCI NIH HHS
ID : F31 CA254138
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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