A SRC-slug-TGFβ2 signaling axis drives poor outcomes in triple-negative breast cancers.

Autor: Angel CZ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Beattie S; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Hanif EAM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Ryan MP; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Guerra Liberal FDC; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Zhang SD; C-TRIC Building, Altnagelvin Area Hospital, Ulster University, Derry, Northern Ireland., Monteith S; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Buckley NE; School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland., Parker E; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Haynes S; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., McIntyre AJ; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Haddock P; School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland., Sharifova M; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Branco CM; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland., Mullan PB; Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland. p.mullan@qub.ac.uk.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Sep 26; Vol. 22 (1), pp. 454. Date of Electronic Publication: 2024 Sep 26.
DOI: 10.1186/s12964-024-01793-6
Abstrakt: Background: Treatment options for the Triple-Negative Breast Cancer (TNBC) subtype remain limited and the outcome for patients with advanced TNBC is very poor. The standard of care is chemotherapy, but approximately 50% of tumors develop resistance.
Methods: We performed gene expression profiling of 58 TNBC tumor samples by microarray, comparing chemosensitive with chemoresistant tumors, which revealed that one of the top upregulated genes was TGFβ2. A connectivity mapping bioinformatics analysis predicted that the SRC inhibitor Dasatinib was a potential pharmacological inhibitor of chemoresistant TNBCs. Claudin-low TNBC cell lines were selected to represent poor-outcome, chemoresistant TNBC, for in vitro experiments and in vivo models.
Results: In vitro, we identified a signaling axis linking SRC, AKT and ERK2, which in turn upregulated the stability of the transcription factors, Slug and Snail. Slug was shown to repress TGFβ2-antisense 1 to promote TGFβ2 signaling, upregulating cell survival via apoptosis and DNA-damage responses. Additionally, an orthotopic allograft in vivo model demonstrated that the SRC inhibitor Dasatinib reduced tumor growth as a single agent, and enhanced responses to the TNBC mainstay drug, Epirubicin.
Conclusion: Targeting the SRC-Slug-TGFβ2 axis may therefore lead to better treatment options and improve patient outcomes in this highly aggressive subpopulation of TNBCs.
(© 2024. The Author(s).)
Databáze: MEDLINE
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