The F-Box Domain-Dependent Activity of EMI1 Regulates PARPi Sensitivity in Triple-Negative Breast Cancers.

The BRCA1-BRCA2-RAD51 axis is essential for homologous recombination repair (HRR) and is frequently disrupted in breast cancers. PARP inhibitors (PARPis) are used clinically to treat BRCA-mutated breast tumors. Using a genetic screen, we identified EMI1 as a modulator of PARPi sensitivity in triple-negative breast cancer (TNBC) cells. This function requires the F-box domain of EMI1, through which EMI1 assembles a canonical SCF ubiquitin ligase complex that constitutively targets RAD51 for degradation. In response to genotoxic stress, CHK1-mediated phosphorylation of RAD51 counteracts EMI1-dependent degradation by enhancing RAD51's affinity for BRCA2, leading to RAD51 accumulation. Inhibition of RAD51 degradation restores HRR in BRCA1-depleted cells. Human breast cancer samples display an inverse correlation between EMI1 and RAD51 protein levels. A subset of BRCA1-deficient TNBC cells develop resistance to PARPi by downregulating EMI1 and restoring RAD51-dependent HRR. Notably, reconstitution of EMI1 expression reestablishes PARPi sensitivity both in cellular systems and in an orthotopic mouse model.

Marzio A ，Puccini J ，Kwon Y ，Maverakis NK ，Arbini A ，Sung P ，Bar-Sagi D ，Pagano M ... -  《-》

Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells.

Moustafa D ，Elwahed MRA ，Elsaid HH ，Parvin JD ... -  《PLoS One》

Prexasertib treatment induces homologous recombination deficiency and synergizes with olaparib in triple-negative breast cancer cells.

Mani C ，Jonnalagadda S ，Lingareddy J ，Awasthi S ，Gmeiner WH ，Palle K ... -  《-》

RAD51 Mediates Resistance of Cancer Stem Cells to PARP Inhibition in Triple-Negative Breast Cancer.

PARP inhibitors have shown promising results in early studies for treatment of breast cancer susceptibility gene (BRCA)-deficient breast cancers; however, resistance ultimately develops. Furthermore, the benefit of PARP inhibitors (PARPi) in triple-negative breast cancers (TNBC) remains unknown. Recent evidence indicates that in TNBCs, cells that display "cancer stem cell" properties are resistant to conventional treatments, mediate tumor metastasis, and contribute to recurrence. The sensitivity of breast cancer stem cells (CSC) to PARPi is unknown. We determined the sensitivity of breast CSCs to PARP inhibition in BRCA1-mutant and -wild-type TNBC cell lines and tumor xenografts. We also investigated the role of RAD51 in mediating CSC resistance to PARPi in these in vitro and in vivo models. We demonstrated that the CSCs in BRCA1-mutant TNBCs were resistant to PARP inhibition, and that these cells had both elevated RAD51 protein levels and activity. Downregulation of RAD51 by shRNA sensitized CSCs to PARP inhibition and reduced tumor growth. BRCA1-wild-type cells were relatively resistant to PARP inhibition alone, but reduction of RAD51 sensitized both CSC and bulk cells in these tumors to PARPi treatment. Our data suggest that in both BRCA1-mutant and BRCA1-wild-type TNBCs, CSCs are relatively resistant to PARP inhibition. This resistance is mediated by RAD51, suggesting that strategies aimed at targeting RAD51 may increase the therapeutic efficacy of PARPi. Clin Cancer Res; 23(2); 514-22. ©2016 AACR.

Liu Y ，Burness ML ，Martin-Trevino R ，Guy J ，Bai S ，Harouaka R ，Brooks MD ，Shang L ，Fox A ，Luther TK ，Davis A ，Baker TL ，Colacino J ，Clouthier SG ，Shao ZM ，Wicha MS ，Liu S ... -  《-》

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Cruz C ，Castroviejo-Bermejo M ，Gutiérrez-Enríquez S ，Llop-Guevara A ，Ibrahim YH ，Gris-Oliver A ，Bonache S ，Morancho B ，Bruna A ，Rueda OM ，Lai Z ，Polanska UM ，Jones GN ，Kristel P ，de Bustos L ，Guzman M ，Rodríguez O ，Grueso J ，Montalban G ，Caratú G ，Mancuso F ，Fasani R ，Jiménez J ，Howat WJ ，Dougherty B ，Vivancos A ，Nuciforo P ，Serres-Créixams X ，Rubio IT ，Oaknin A ，Cadogan E ，Barrett JC ，Caldas C ，Baselga J ，Saura C ，Cortés J ，Arribas J ，Jonkers J ，Díez O ，O'Connor MJ ，Balmaña J ，Serra V ... -  《-》