학술논문
Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Document Type
article
Author
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
Source
Nature Communications, Vol 14, Iss 1, Pp 1-22 (2023)
Subject
Language
English
ISSN
2041-1723
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.