Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer. Clin Cancer Res 2023 Sep 15;29(18):3717-3728
Date
07/13/2023Pubmed ID
37439680Pubmed Central ID
PMC10528687DOI
10.1158/1078-0432.CCR-23-0488Scopus ID
2-s2.0-85168258598 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
PURPOSE: Clinical evidence indicates that treatment with estrogens elicits anticancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor α (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains underused. Mechanistic understanding may offer strategies to enhance therapeutic efficacy.
EXPERIMENTAL DESIGN: We performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17β-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDX), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models.
RESULTS: Cells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacologic suppression of the DNA damage response via PARP inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2-mutant and BRCA1/2-wild-type cell line and PDX models.
CONCLUSIONS: E2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.
Author List
Traphagen NA, Schwartz GN, Tau S, Roberts AM, Jiang A, Hosford SR, Marotti JD, Goen AE, Romo BA, Johnson AL, Duffy EK, Demidenko E, Heverly P, Mosesson Y, Soucy SM, Kolling F, Miller TWAuthor
Todd W. Miller PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
BRCA1 ProteinBRCA2 Protein
Breast Neoplasms
Cell Line, Tumor
DNA Damage
Estrogen Receptor alpha
Estrogens
Female
Humans
Neoplasm Recurrence, Local
Poly(ADP-ribose) Polymerase Inhibitors
