Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer

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 and Eldad Zacksenhaus ()
Additional contact information
Zhe Jiang: Toronto General Research Institute - University Health Network
YoungJun Ju: Toronto General Research Institute - University Health Network
Amjad Ali: Toronto General Research Institute - University Health Network
Philip E. D. Chung: Toronto General Research Institute - University Health Network
Patryk Skowron: University of Toronto
Dong-Yu Wang: Toronto General Research Institute - University Health Network
Mariusz Shrestha: Toronto General Research Institute - University Health Network
Huiqin Li: Toronto General Research Institute - University Health Network
Jeff C. Liu: University of Toronto
Ioulia Vorobieva: Toronto General Research Institute - University Health Network
Ronak Ghanbari-Azarnier: Toronto General Research Institute - University Health Network
Ethel Mwewa: Toronto General Research Institute - University Health Network
Marianne Koritzinsky: University Health Network
Yaacov Ben-David: The Key laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences
James R. Woodgett: Sinai Health System
Charles M. Perou: University of North Carolina
Adam Dupuy: The University of Iowa
Gary D. Bader: University of Toronto
Sean E. Egan: The Hospital for Sick Children
Michael D. Taylor: University of Toronto
Eldad Zacksenhaus: Toronto General Research Institute - University Health Network

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39935-y

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