TUFT1 promotes metastasis and chemoresistance in triple negative breast cancer through the TUFT1/Rab5/Rac1 pathway

Abstract

Background Triple 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. Methods We 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. Results TUFT1 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. Conclusions Our findings suggest that the TUFT1/Rab5/Rac1 pathway may be a potential target for the effective treatment of TNBC.

Tuftelin 1 (TUFT1) Promotes the Proliferation and Migration of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway

“…However, in lung cancer cells, TUFT1 seems to enhance tumorigenesis through mTORC1 signaling pathway [ 39 ]. In addition, in breast cancer, TUFT1 promotes metastasis and chemoresistance through Rab5/Rac1 pathway [ 21 ]. These findings indicate that TUFT1 exerts oncogenic functions in different cancers, but the underlying mechanisms may differ.…”

“…Recently, TUFT1 expression is reported to be elevated in several types of cancers including hepatocellular carcinoma (HCC), breast cancer, thyroid carcinoma and osteosarcoma [18][19][20]. Increased expression of TUFT1 can promote the growth and metastasis of cancer cells through distinctive pathways in different cancers [20,21]. Moreover, TUFT1 expression is associated with unfavorable clinical outcomes and poor prognosis of HCC [20].…”

ATF2 accelerates the invasion and metastasis of hepatocellular carcinoma through targeting the miR‐548p/TUFT1 axis

“…TUFT1 has been demonstrated to be a key regulator in various cancers including breast cancer, pancreatic carcinoma and lung adenocarcinoma. 23,37,38 Our results indicated that the ATF2/miR-548p-mediated suppressive effects in HCC were dependent on controlling TUFT1 expression. Combined with other results and literatures, we speculated that ATF2/miR-548p/TUFT1 axis regulates HCC progression.…”

Identification of a Novel Epithelial–Mesenchymal Transition-Related Gene Signature for Endometrial Carcinoma Prognosis

“…CDKN2A was found to be inactivated in EC and its hypermethylation was correlated with an increased risk of EC [ 26 , 27 ]. The HER2 (ERBB2) gene is amplified in 17–33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors [ 28 , 29 ]. However, for the remaining genes, their functions have not been revealed in EC.…”