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.

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miR-9-5p Promotes β-Catenin-Activated Epithelial-To-Mesenchymal Transition of Triple-Negative Breast Cancer Via Targeting LZTS2

10.21203/rs.3.rs-105343/v1 ◽

2020 ◽

Author(s):

Jie Zhang ◽

Lina Zhang ◽

Jianlong Wang ◽

Jing Zhao ◽

Xuelian Zhao ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Suppressor ◽

Triple Negative Breast Cancer ◽

Nuclear Export ◽

Triple Negative ◽

Tumor Model ◽

Migration And Invasion ◽

Xenograft Tumor ◽

Xenograft Tumor Model ◽

Low Expression

Abstract Background: Leucine zipper tumor suppressor 2 (LZTS2), an emerging tumor-suppressor, is attenuated in multiple cancers including prostate, lung and colon cancer. However, its expression and upstream regulatory mechanisms in triple negative breast cancer (TNBC) still remain unknown.Materials and methods: The expression of LZTS2 in TNBC and matched para-carcinoma tissues was detected with immunohistochemistry. The correlations between LZTS2 expression and clinicopathological parameters were analyzed. Kaplan-Meier analysis was performed to determine the prognostic role of LZTS2 for TNBC patients. CCK-8, wound healing and transwell assay were used to detect the effect of LZTS2 overexpression on the proliferation, migration and invasion ability, respectively. The bioinformation algorithms were used to reveal the potential upstream regulatory miRNA. Then, dual-luciferase reporter assay was performed to confirm the regulatory effect of the chosen miRNA on the expression of LZTS2. miR-9-5p inhibitor was used to determine the effect of miR-9-5p on the subcellular localization of β-catenin. Then, western blotting was performed to reveal the effect of miR-9-5p on EMT-related proteins in TNBC cells. Xenograft tumor model was established to reveal the effect of miR-9-5p on TNBC progression in vivo.Results: Low expression of LZTS2 was observed in 62 of 95 cases of TNBC tissue. Low expression of LZTS2 was correlated with poor postoperative DFS and OS of TNBC patients. LZTS2 could inhibit the proliferation, migration and invasion ability of TNBC cells. LZTS2 could be downregulated by miR-9-5p in TNBC, and the nuclear export of β-catenin was suppressed. Consequently, miR-9-5p inhibitor downregulated E-cadherin and upregulated N-cadherin, Twist and Vimentin in TNBC cells. Xenograft tumor model showed that miR-9-5p inhibitor could upregulate the expression of LZTS2 and induce nuclear export of β-catenin in TNBC.Conclusions: miR-9-5p contributes to β-catenin-activated EMT via downregulating LZTS2, and thus promotes TNBC progression.

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Abstract P3-01-16: Utilizing a decellularized patient-derived xenograft tumor model for the evaluation of triple negative breast cancer

10.1158/1538-7445.sabcs19-p3-01-16 ◽

2020 ◽

Author(s):

Maryl Wright ◽

Margarite Matossian ◽

Connor King ◽

Khoa Nguyen ◽

Steven Elliott ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Tumor Model ◽

Xenograft Tumor ◽

Patient Derived Xenograft ◽

Xenograft Tumor Model

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Unraveling the role of CDK8 in triple-negative breast cancer metastasis

Intrinsic Activity ◽

10.25006/ia.6.s1-a4.2 ◽

2018 ◽

Vol 6 (Suppl. 1) ◽

pp. A4.2

Author(s):

Vanessa M. Knab

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis

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19P A dichotomous oncogenic role of the splicing factor SF3A3 in MYC-driven triple-negative breast cancer

Annals of Oncology ◽

10.1016/j.annonc.2021.03.033 ◽

2021 ◽

Vol 32 ◽

pp. S28

Author(s):

A. Bosch ◽

M. Cieśla ◽

P. Cao Thi Ngoc ◽

S. Mutukumar ◽

G. Honeth ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Splicing Factor

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The Relevance of the SH2 Domain for c-Src Functionality in Triple-Negative Breast Cancer Cells

Cancers ◽

10.3390/cancers13030462 ◽

2021 ◽

Vol 13 (3) ◽

pp. 462

Author(s):

Víctor Mayoral-Varo ◽

María Pilar Sánchez-Bailón ◽

Annarica Calcabrini ◽

Marta García-Hernández ◽

Valerio Frezza ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Sh2 Domain ◽

Model Systems ◽

System A ◽

Promising Therapeutic Target ◽

Relevant Role ◽

Inactivating Mutation

The role of Src family kinases (SFKs) in human tumors has been always associated with tyrosine kinase activity and much less attention has been given to the SH2 and SH3 adapter domains. Here, we studied the role of the c-Src-SH2 domain in triple-negative breast cancer (TNBC). To this end, SUM159PT and MDA-MB-231 human cell lines were employed as model systems. These cells conditionally expressed, under tetracycline control (Tet-On system), a c-Src variant with point-inactivating mutation of the SH2 adapter domain (R175L). The expression of this mutant reduced the self-renewal capability of the enriched population of breast cancer stem cells (BCSCs), demonstrating the importance of the SH2 adapter domain of c-Src in the mammary gland carcinogenesis. In addition, the analysis of anchorage-independent growth, proliferation, migration, and invasiveness, all processes associated with tumorigenesis, showed that the SH2 domain of c-Src plays a very relevant role in their regulation. Furthermore, the transfection of two different aptamers directed to SH2-c-Src in both SUM159PT and MDA-MB-231 cells induced inhibition of their proliferation, migration, and invasiveness, strengthening the hypothesis that this domain is highly involved in TNBC tumorigenesis. Therefore, the SH2 domain of c-Src could be a promising therapeutic target and combined treatments with inhibitors of c-Src kinase enzymatic activity may represent a new therapeutic strategy for patients with TNBC, whose prognosis is currently very negative.

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49P The role of circulating cell-free DNA measured by a simple fluorescent assay to predict relapse in triple negative breast cancer receiving neoadjuvant chemotherapy

Annals of Oncology ◽

10.1016/s0923-7534(21)00209-x ◽

2016 ◽

Vol 27 ◽

pp. ix14

Author(s):

K. Park ◽

M. Woo ◽

J.E. Kim ◽

J.-H. Ahn ◽

K.H. Jung ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Fluorescent Assay ◽

Cell Free Dna ◽

Free Dna ◽

Circulating Cell Free Dna

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Antiproliferative Effect of Androgen Receptor Inhibition in Mesenchymal Stem-Like Triple-Negative Breast Cancer

Cellular Physiology and Biochemistry ◽

10.1159/000443052 ◽

2016 ◽

Vol 38 (3) ◽

pp. 1003-1014 ◽

Cited By ~ 24

Author(s):

Aiyu Zhu ◽

Yan Li ◽

Wei Song ◽

Yumei Xu ◽

Fang Yang ◽

...

Keyword(s):

Breast Cancer ◽

Androgen Receptor ◽

Cyclin D1 ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative

Background/Aims: Androgen receptor (AR), a steroid hormone receptor, has recently emerged as prognostic and treatment-predictive marker in breast cancer. Previous studies have shown that AR is widely expressed in up to one-third of triple-negative breast cancer (TNBC). However, the role of AR in TNBC is still not fully understood, especially in mesenchymal stem-like (MSL) TNBC cells. Methods: MSL TNBC MDA-MB-231 and Hs578T breast cancer cells were exposed to various concentration of agonist 5-α-dihydrotestosterone (DHT) or nonsteroidal antagonist bicalutamide or untreated. The effects of AR on cell viability and apoptosis were determined by MTT assay, cell counting, flow cytometry analysis and protein expression of p53, p73, p21 and Cyclin D1 were analyzed by western blotting. The bindings of AR to p73 and p21 promoter were detected by ChIP assay. MDA-MB-231 cells were transplanted into nude mice and the tumor growth curves were determined and expression of AR, p73 and p21 were detected by Immunohistochemistry (IHC) staining after treatment of DHT or bicalutamide. Results: We demonstrate that AR agonist DHT induces MSL TNBC breast cancer cells proliferation and inhibits apoptosis in vitro. Similarly, activated AR significantly increases viability of MDA-MB-231 xenografts in vivo. On the contrary, AR antagonist, bicalutamide, causes apoptosis and exerts inhibitory effects on the growth of breast cancer. Moreover, DHT-dependent activation of AR involves regulation in the cell cycle related genes, including p73, p21 and Cyclin D1. Further investigations indicate the modulation of AR on p73 and p21 mediated by direct binding of AR to their promoters, and DHT could make these binding more effectively. Conclusions: Our study demonstrates the tumorigenesis role of AR and the inhibitory effect of bicalutamide in AR-positive MSL TNBC both in vitro and in vivo, suggesting that AR inhibition could be a potential therapeutic approach for AR-positive TNBC patients.

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Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation

Cancers ◽

10.3390/cancers13133357 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3357

Author(s):

Hongmei Zheng ◽

Sumit Siddharth ◽

Sheetal Parida ◽

Xinhong Wu ◽

Dipali Sharma

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Treatment Options ◽

Combined Treatment ◽

High Mobility ◽

Sphingosine 1 Phosphate ◽

Molecular Patterns

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.

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