Triumphs and challenges in exploiting poly(ADP‐ribose) polymerase inhibition to combat triple‐negative breast cancer

Poly(ADP‐ribose) polymerase 1 (PARP1) regulates a myriad of DNA repair mechanisms to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) confer synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Patients with triple‐negative breas...

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Published in:Journal of cellular physiology 2023-08, Vol.238 (8), p.1625-1640
Main Authors: Wooten, Jonathan, Mavingire, Nicole, Damar, Katherine, Loaiza‐Perez, Andrea, Brantley, Eileen
Format: Article
Language:English
Subjects:
Adenosine diphosphate
BRCA1 protein
BRCA2 protein
Breast cancer
Deoxyribonucleic acid
DNA
DNA damage
DNA damage repair
DNA repair
Epithelial cells
Epithelium
Estrogen receptors
Estrogens
Growth factors
Homologous recombination
Lethality
Malignancy
PARP inhibitor resistance
poly(ADP)‐ribose polymerase (PARP)
Poly(ADP-ribose) polymerase
Progesterone
Receptors
Ribose
synthetic lethality
triple‐negative breast cancer
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Summary:Poly(ADP‐ribose) polymerase 1 (PARP1) regulates a myriad of DNA repair mechanisms to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) confer synthetic lethality in malignancies with a deficiency in the homologous recombination (HR) pathway. Patients with triple‐negative breast cancer (TNBC) fail to respond to most targeted therapies because their tumors lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Certain patients with TNBC harbor mutations in HR mediators such as breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2), enabling them to respond to PARPi. PARPi exploits the synthetic lethality of BRCA‐mutant cells. However, de novo and acquired PARPi resistance frequently ensue. In this review, we discuss the roles of PARP in mediating DNA repair processes in breast epithelial cells, mechanisms of PARPi resistance in TNBC, and recent advances in the development of agents designed to overcome PARPi resistance in TNBC.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.31015