| Autor: |
Zhe Jiang, YoungJun Ju, Amjad Ali, Philip E. D. Chung, Patryk Skowron, Dong-Yu Wang, Mariusz Shrestha, Huiqin Li, Jeff C. Liu, Ioulia Vorobieva, Ronak Ghanbari-Azarnier, Ethel Mwewa, Marianne Koritzinsky, Yaacov Ben-David, James R. Woodgett, Charles M. Perou, Adam Dupuy, Gary D. Bader, Sean E. Egan, Michael D. Taylor, Eldad Zacksenhaus |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 14, Iss 1, Pp 1-22 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-023-39935-y |
| Popis: |
Abstract Metastatic breast-cancer is a major cause of death in women worldwide, yet the relationship between oncogenic drivers that promote metastatic versus primary cancer is still contentious. To elucidate this relationship in treatment-naive animals, we hereby describe mammary-specific transposon-mutagenesis screens in female mice together with loss-of-function Rb, which is frequently inactivated in breast-cancer. We report gene-centric common insertion-sites (gCIS) that are enriched in primary-tumors, in metastases or shared by both compartments. Shared-gCIS comprise a major MET-RAS network, whereas metastasis-gCIS form three additional hubs: Rho-signaling, Ubiquitination and RNA-processing. Pathway analysis of four clinical cohorts with paired primary-tumors and metastases reveals similar organization in human breast-cancer with subtype-specific shared-drivers (e.g. RB1-loss, TP53-loss, high MET, RAS, ER), primary-enriched (EGFR, TGFβ and STAT3) and metastasis-enriched (RHO, PI3K) oncogenic signaling. Inhibitors of RB1-deficiency or MET plus RHO-signaling cooperate to block cell migration and drive tumor cell-death. Thus, targeting shared- and metastasis- but not primary-enriched derivers offers a rational avenue to prevent metastatic breast-cancer. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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