Targeting IRAK2 in triple-negative breast cancer cells decreases cellular growth in vitro and delays tumor progression in murine models

ABSTRACT: Breast cancer stem cells (BCSCs) are responsible for tumor recurrence and therapy resistance. We have established primary BCSC cultures from human tumors of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs generate xenografts phenocopying the tumors of origin, representing a suitable model to investigate breast cancer targeting strategies. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Since IRAK2 is highly enriched in primary BCSCs we wondered if its depletion could affect their growth. Primary BCSCs and MDA-MB-468 presenting IRAK2 downregulation exhibited decreased proliferation and sphere-forming capacity, evidencing the role of IRAK2 in cellular growth and self-renewal. When transplanted orthotopically into immunocompromised mice, IRAK2 knockdown cells originated smaller xenografts in comparison with control cells, suggesting that IRAK2 downregulation may delay tumor development. Investigating the molecular pathways affected by the knockdown, NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signaling and autophagy were decreased in a cell line-dependent way. Transcriptome analysis confirmed that the cells were to some extent differently affected by the knockdown, indicating that their heterogeneity, different mutations, genetic background, expression of IRAK2 and level of its downregulation could influence the outcome of the knockdown. Given that overall IRAK2 downregulation decreased cellular ability to sustain aggressive growth and to endure cellular stress, IRAK2 may be considered an interesting target to compromise TNBC progression, positively contributing to TNBC clinical outcome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE213228 | GEO | 2022/09/15

REPOSITORIES: GEO