Journal article
Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
Nature communications, Vol.14(1), 4313
07/18/2023
DOI: 10.1038/s41467-023-39935-y
PMCID: PMC10354065
PMID: 37463901
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.
Distinguishing the drivers of metastasis versus those of the primary tumour in breast cancer remains challenging. Here, the authors explore primary-only, metastatic-only, and shared drivers in breast cancer using mammary-specific transposon mutagenesis screens, which leads to potential therapeutic targets to prevent metastasis.
Details
- Title: Subtitle
- Distinct shared and compartment-enriched oncogenic networks drive primary versus metastatic breast cancer
- Creators
- Zhe Jiang - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaYoungJun Ju - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaAmjad Ali - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaPhilip E. D. Chung - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 Canada Toronto, ON CanadaPatryk Skowron - Toronto, ON Canada Toronto, ON Canada Toronto, ON CanadaDong-Yu Wang - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaMariusz Shrestha - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 Canada Toronto, ON CanadaHuiqin Li - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaJeff C. Liu - Toronto, ON CanadaIoulia Vorobieva - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 Canada Toronto, ON CanadaRonak Ghanbari-Azarnier - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 Canada Toronto, ON CanadaEthel Mwewa - 101 College Street, Max Bell Research Centre, suite 5R406, Toronto, ON M5G 1L7 CanadaMarianne Koritzinsky - Toronto, ON CanadaYaacov Ben-David - The Key laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou 550014 China Guiyang, 550025 ChinaJames R. Woodgett - 600 University Avenue, Toronto, ON CanadaCharles M. Perou - Chapel Hill, NC 27599 USAAdam Dupuy - Iowa City, Iowa 52242 USAGary D. Bader - Toronto, ON Canada Toronto, ON CanadaSean E. Egan - Toronto, ON Canada Toronto, ON CanadaMichael D. Taylor - Toronto, ON Canada Toronto, ON Canada Toronto, ON CanadaEldad Zacksenhaus - Bell (Canada)
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.14(1), 4313
- DOI
- 10.1038/s41467-023-39935-y
- PMID
- 37463901
- PMCID
- PMC10354065
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- ;
- Language
- English
- Date published
- 07/18/2023
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984445545402771
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