Abstract
BackgroundTriple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis. However, the specific mechanisms underlying these phenotypes are unclear. TUFT1 plays an important role in BC and impacts the proliferation and survival of BC cells. Recent studies have shown that TUFT1 mediates intracellular lysosome localization and vesicle transport by regulating Rab GTPase, but the relevance of this activity in TNBC is unknown. Therefore, our aim was to systematically study the role of TUFT1 in the metastasis and chemoresistance of TNBC.MethodsWe measured TUFT1, Rab5-GTP, and Rac1-GTP expression levels in samples of human TNBC by immunohistochemistry (IHC) and conducted univariate and multivariate analyses. shRNA-mediated knockdown and overexpression, combined with transwell assays, co-immunoprecipitation, a nude mouse xenograft tumor model, and GTP activity assays were used for further mechanistic studies.ResultsTUFT1 expression was positively correlated with Rab5-GTP and Rac1-GTP in the TNBC samples, and co-expression of TUFT1 and Rab5-GTP predicted poor prognosis in TNBC patients who were treated with chemotherapy. Mechanism studies showed that TUFT1 could activate Rab5 by binding to p85α, leading to activation of Rac1 through recruitment of Tiam1, and concurrent down-regulation of the NF-κB pathway and proapoptotic factors, ultimately promoting metastasis and chemoresistance in TNBC cells.ConclusionsOur findings suggest that the TUFT1/Rab5/Rac1 pathway may be a potential target for the effective treatment of TNBC.
Highlights
Triple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis
We investigated the role of TUFT1, Rab5, and Rac1 in the metastasis and chemoresistance of TNBC cells, with the aim of evaluating TUFT1 as a prognostic and therapeutic target for TNBC
TUFT1 and Rab5‐GTP expression are positively correlated and predict poor prognosis after chemotherapy in patients with TNBC In the TNBC samples, TUFT1 staining was mainly observed in the cytoplasm and cytomembrane, with the strongest staining in the cytoplasm
Summary
Triple negative breast cancer (TNBC) is a breast cancer (BC) subtype that is characterized by its strong invasion and a high risk of metastasis. TUFT1 plays an important role in BC and impacts the proliferation and survival of BC cells. Zhou et al [5] demonstrated that TUFT1 protein is highly expressed in pancreatic cancer and that its expression correlates with both disease stage and local lymph node metastasis. They proposed that TUFT1 may affect HIF1 by influencing the expression of components of the Snail signaling pathway, which regulates epithelial mesenchymal transition. Recent studies have shown that TUFT1 promotes the proliferation, metastasis, and epithelialmesenchymal transformation of hepatocellular carcinoma cells through the C a2+/PI3 K/AKT pathway. We showed that inhibiting TUFT1 expression altered the gene expression of Rab, Rac, p65, and caspase 3 [7, 8]
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