Mutant p53 Directs PARP to Regulate Replication Stress and Drive Breast Cancer Metastasis - PubMed
6 hours ago
- #breast cancer metastasis
- #PARP inhibitor
- #mutant p53
- TP53 mutations occur in 80-90% of triple-negative breast cancers (TNBCs) and drive genomic instability and metastasis.
- Mutant p53 (mtp53) associates with chromatin and PARP, enhancing PARP recruitment to replication forks to support S phase progression.
- The C-terminal domain of mtp53 is critical for its interaction with PARP and Poly (ADP-ribose) (PAR), facilitating tumor growth and metastasis.
- Combination therapy with PARP inhibitor talazoparib (TAL) and alkylating agent temozolomide (TMZ) selectively kills mtp53-expressing breast cancer cells and organoids.
- In preclinical models, TAL+TMZ treatment reduces circulating tumor cells, lung metastases, and metastasis-promoting proteins like MDMX in mtp53 tumors.
- Deletion of the mtp53 C-terminal domain impairs replication fork progression, tumor growth, and metastasis, highlighting its tumor-promoting role.
- Mutant p53 exploits PARP to enable adaptation to replication stress, making it a predictive biomarker for PARP inhibitor-based therapies in TNBC.