Pub. Date : 2015 Jan 13
PMID : 25583261
8 Functional Relationships(s)Download |
Sentence | Compound Name | Protein Name | Organism |
| 1 | BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 2 | Here we investigate the role of BRCA1-IRIS as a novel treatment target for TNBCs and their paclitaxel-resistant recurrences. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 3 | METHODS: We analyzed the response of BRCA1-IRIS overexpressing normal mammary cells or established TNBC cells silenced from BRCA1-IRIS to paclitaxel in vitro and in vivo. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 4 | We analyzed BRCA1-IRIS downstream signaling pathways in relation to paclitaxel treatment. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 5 | RESULTS: We show that low concentrations of paclitaxel triggers BRCA1-IRIS expression in vitro and in vivo, and that BRCA1-IRIS activates two autocrine signaling loops (epidermal growth factor (EGF)/EGF receptor 1 (EGFR)-EGF receptor 2 (ErbB2) and neurogulin 1 (NRG1)/ErbB2-EGF receptor 3 (ErbB3), which enhances protein kinase B (AKT) and thus survivin expression/activation through promoting FOXO3a degradation. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 6 | These events trigger the intrinsic and acquired paclitaxel resistance phenotype known for BRCA1-IRIS-overexpressing TNBCs. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 7 | Inactivating BRCA1-IRIS signaling using a novel inhibitory mimetic peptide inactivates these autocrine loops, AKT and survivin activity/expression, in part by restoring FOXO3a expression, and sensitizes TNBC cells to low paclitaxel concentrations in vitro and in vivo. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |
| 8 | CONCLUSIONS: In addition to driving TNBC tumor formation, BRCA1-IRIS overexpression drives their intrinsic and acquired paclitaxel resistance, partly by activating autocrine signaling loops EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3. | Paclitaxel | BRCA1 DNA repair associated | Homo sapiens |