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

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.

Thinking (Metastasis) outside the (Primary Tumor) Box

“…To address this issue, our group has recently conducted a transposon-based (Sleeping Beauty) mutagenesis screen on drug-naïve, retinoblastoma Rb-deficient genetic background [20] and identified oncogenic drivers in the primary (mammary gland) and metastatic (lung) compartments [21]. We used conditional Rb-mutant mice because the RB tumor suppressor is frequently disrupted in breast cancer either genetically via oncogenic alterations such as mutations/deletions/promoter methylation of the gene or functionally through over-phosphorylation of the pRB protein via cyclin-dependent kinases CDK4/6 and CDK2 [22][23][24].…”

“…The shared oncogenic drivers comprised a major MET-RAS hub (Met, Prlr, Nf1, Map3k3, Stat5b, and Notch1) known to promote tumor growth and cell migration [30][31][32], as well as Jup/Plakoglobin/gamma-catenin, involved in collective cell migration [33]. The metastasis-specific drivers formed three additional hubs: Rho signaling (migration; Srgap2, Cdc42bpa/Mrcka, and Wasf2/Wave2), ubiquitination (e.g., Fbxw4, Ubxn7, Spop, Hectd1, and Ube2d3) and RNA processing (Wdr33, Cwc22, Cdc5l, Prpf6, and Pspc1) [21]. We showed that the expression of these metastatic hub genes correlates with poor prognosis in breast cancer and validated representatives of each hub for promoting hallmarks of metastasis such as cell migration, as well as cell proliferation and/or tumorigenesis.…”

“…To ask whether similar organization occurs in breast cancer patients, we calculated the pathway activity of 26 different oncogenic signaling in several independent cohorts of paired primary and metastatic breast lesions [21,[34][35][36][37]. We found a parallel organization with subtype-specific shared oncogenic drivers (e.g., RB1-loss, TP53-loss, high MET, MYC, ER) and across subtypes primary-enriched (EGFR, TGFb, and STAT3) and metastasis-enriched (RHO and PI3K) signaling [21]. These results are consistent with previous observations that the EGFR, TGFb, and STAT3 pathways exhibit opposing effects on primary vs. metastatic cancers [38][39][40][41][42][43].…”

“…First, in line with the title of this Editorial, the therapeutic importance of oncogenic drivers that promote primary cancer (for tumors such as breast cancer that are surgically removed) can only be appreciated by understanding their impact on metastasis. Second, targeting shared-and metastasisenriched or -specific but not primary-enriched drivers represents a rational strategy to prevent metastases at the time of primary tumor detection [21]. Primary tumor cells (left) evolve via a Darwinian process that selects tumor cell clones (e.g., yellow cells) with the ability to rapidly proliferate, survive, and dominate the primary tumor population locally.…”