Differential DNA damage repair and PARP inhibitor vulnerability of the mammary epithelial lineages

It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial cell lineage identity. Bioinformatics, post-ir...

Descripción completa

Detalles Bibliográficos
Autores: Kim, Hyeyeon, Aliar, Kazeera, Tharmapalan, Pirashaanthy, Mccloskey, Curtis W., Kuttanamkuzhi, Abhijith, Grünwald, Barbara T., Palomero, Luis, Mahendralingam, Mathepan J., Waas, Matthew, Mer, Arvind S., Elliott, Mitchell J., Zhang, Bowen, Al-Zahrani, Khalid N., Langille, Ellen R., Parsons, Michael, Narala, Swami, Hofer, Stefan, Waterhouse, Paul D., Hakem, Razq, Haibe-Kains, Benjamin, Kislinger, Thomas, Schramek, Daniel, Cescon, David W., Pujana Genestar, M. Ángel, Berman, Hal K., Khokha, Rama
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/204202
Acceso en línea:https://hdl.handle.net/2445/204202
Access Level:acceso abierto
Palabra clave:Càncer de mama
Inhibidors enzimàtics
Breast cancer
Enzyme inhibitors
Descripción
Sumario:It is widely assumed that all normal somatic cells can equally perform homologous recombination (HR) and non-homologous end joining in the DNA damage response (DDR). Here, we show that the DDR in normal mammary gland inherently depends on the epithelial cell lineage identity. Bioinformatics, post-irradiation DNA damage repair kinetics, and clonogenic assays demonstrated luminal lineage exhibiting a more pronounced DDR and HR repair compared to the basal lineage. Consequently, basal progenitors were far more sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis) in both mouse and human mammary epithelium. Furthermore, PARPi sensitivity of murine and human breast cancer cell lines as well as patient derived xenografts correlated with their molecular resemblance to the mammary progenitor lineages. Thus, mammary epithelial cells are intrinsically divergent in their DNA damage repair capacity and PARPi vulnerability, potentially influencing the clinical utility of this targeted therapy.

Similares en LA Referencia