scholarly journals ARF6–JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion

2015 ◽  
Vol 211 (2) ◽  
pp. 339-358 ◽  
Author(s):  
Valentina Marchesin ◽  
Antonio Castro-Castro ◽  
Catalina Lodillinsky ◽  
Alessia Castagnino ◽  
Joanna Cyrta ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Cell Biology ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Breast Cancers ◽  
Interacting Protein ◽  
Membrane Type ◽  
Syndrome Protein

Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1–matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase–interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein–dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin–dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6–JIP–MT1-MMP–dynein–dynactin–kinesin-1 axis promoting an invasive phenotype of breast cancer cells.

Using epigenetic reprogramming to target triple-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14565-e14565
Author(s):  
D. Sharma ◽  
B. B. Knight ◽  
R. Yacoub ◽  
T. Liu ◽  
L. Taliaferro-Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hormone Receptors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Brdu Incorporation ◽  
Breast Cancers

e14565 Background: The outcome for patients with breast cancer has been significantly improved by the use of targeted agents. The prognosis of triple negative (TN) breast cancers, which do not express hormone receptors (ER, PR) or Her2, is poor, because of an aggressive clinical course and lack of targeted therapeutic agents. Epigenetic silencing of specific genes has been observed in breast cancer and some of these genes are more important due to available targeted therapies such as ER. Since all endocrine therapies are designed to block ER function in some way, the identification of new therapies or strategies that could sensitize TN breast cancers to existing endocrine therapy could provide a revolutionary means of treating this aggressive subtype of cancer Methods: We examined the efficacy of combined treatment of HDAC inhibitor LBH589 and DNMT inhibitor decitabine to regenerate ER and PR in TN breast cancer cells using RT-PCR and immunoblotting. Changes in growth and proliferation of TN breast cancer cells in response to LBH589 and decitabine treatment were determined by XTT, BrdU incorporation and colony formation assay. Changes in apoptotic proteins were determined by western blotting. Athymic nude mice were used to establish pre-clinical models for TN breast cancer cells and effectiveness of combined treatment of LBH589 and decitabine was determined. Tumors biopsies were analyzed for ER and PR re-expression by western blot analysis and immunohistochemistry at the end of the treatment. Results: Combined treatment of LBH589 and decitabine resulted in re-expression of ER and PR in TN breast cancers in vitro and in vivo. Although re-expression of ER and PR were noted following LBH589 treatment alone, re-expression was more robust with the combination. TN breast cancer cells showing re-expressed ER can be targeted with tamoxifen. Tamoxifen inhibits growth of TN breast cancer cells re- expressing ER by triggering apoptosis. Conclusions: The importance of epigenetic events such as DNA methylation and HDAC inhibition in tumor progression is becoming increasingly evident. A trial evaluating the ability of LBH589 and decitabine to re- express ER, which can then be targeted by tamoxifen, is planned in patients with metastatic TN breast cancer. No significant financial relationships to disclose.

scholarly journals The Deubiquitin Enzyme USP28 Maintains the Viability of Triple Negative Breast Cancer Cells through Stabilizing the RecQ Family Helicases

2021 ◽  
Author(s):  
Jin Peng ◽  
Jiewei Wang ◽  
Yiping Dong ◽  
Huailu Ma ◽  
Lingzhi Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Cell Biology ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Essential Gene ◽  
Critical Role ◽  
Tumor Xenograft

Abstract Background: Triple-negative breast cancer lacks significant expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the more aggressive and malignant kind of breast cancers and is currently without any effective targeted therapies.Methods: We have screened for genes in the ubiquitin-proteasome system that are essential for the proliferation and survival of TNBC cells via CRISPR/Cas9-mediated gene editing. Growth of TNBC cells were assayed using cell and tumor xenograft models to validate the vital role of USP28. We employed cell biology and biochemical methods to uncover the mechanisms underlying the requirement of USP28 for the proliferation of TNBC cells.Results: USP28, a deubiquitin enzyme, is an essential gene for TNBC cells in vitro and in vivo. Compromising the function of USP28 causes TNBC cells to arrest in S/G2 phases with DNA damage checkpoint activation. We show that RecQ family helicases are regulated by USP28, which is more important in TNBC cells than in other breast cancer cells. We further showed that a small molecule inhibitor of USP28 displayed anti-tumor activities against xenografts derived from TNBC cells.Conclusion: Our data establish a critical role played by USP28 in supporting the proliferation and viability of triple negative breast cancer cells through stabilizing RecQ family helicases and support USP28 as a therapeutic target for TNBC.

Effect of mTOR inhibition on sensitivity of triple-negative breast cancer cells to epidermal growth factor inhibition

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1055-1055 ◽  
Author(s):  
T. Liu ◽  
R. Yacoub ◽  
T. Graham ◽  
L. Yang ◽  
M. Tighiouart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Mtor Inhibitors ◽  
Egfr Inhibitors ◽  
Breast Cancers ◽  
Mtor Inhibition

1055 Background: The outcome for patients with triple negative (TN) cancers is poor at least in part because of a lack of targeted therapies. Although 50% of TN breast cancers over-express EGFR, the use of EGFR inhibitors as single agents in patients with unselected and TN metastatic breast cancers has produced disappointing results. Likewise, mTOR inhibitors have modest activity as single agents in metastatic breast cancer. mTOR inhibitors have been demonstrated to activate the Akt pathway by a possible feedback mechanism, which could potentially sensitize TN breast cancer cells to upstream inhibitors. We have previously demonstrated that EGFR inhibitors in combination with rapamycin (RAPA) decrease cell survival, increase apoptosis, and are synergistic in TN breast cancer cells, compared to any of the agents alone (AACR 2008). We, therefore, evaluated the combination of mTOR and EGFR inhibition in vivo. Methods: Athymic mice were inoculated with TN (MDA-MB-231) breast cancer cells. One week after cell inoculation, mice were treated with vehicle, lapatinib 75mg/kg by mouth daily, RAPA 3mg/kg IP biweekly, or the combination. After 4 weeks of treatment, mice were sacrificed and tumors were assessed for target proteins by Western blotting and immunohistochemistry Results: The combination of RAPA and lapatinib resulted in a significant decrease in TN breast tumor volume (76 mm3), compared to rapamycin alone (133 mm3, p = 0.01), lapatinib alone (183 mm3, p < 0.0001) or control (188 mm3, p = 0.005). Neither lapatinib nor RAPA alone inhibited tumor growth significantly compared to control (p > 0.05). Interestingly, in contrast to our findings in vitro, the increase in pAkt noted in RAPA treated tumors was not decreased by lapatinib, despite the significant decrease in tumor size in tumors treated with the combination. Conclusions: These studies demonstrate that the combination of mTOR inhibition and lapatinib significantly inhibit TN breast cancer growth, compared with either agent alone. Given the lack of targeted therapies in TN breast cancers, these data support the possibility that mTOR inhibition can sensitize TN breast cancers to EGFR inhibitors. A clinical trial evaluating the combination of lapatinib and RAD001 as second-line therapy for TN metastatic breast cancer is planned. [Table: see text]

Cytotoxic and apoptotic effects of ternary silver(i) complexes bearing 2-formylpyridine thiosemicarbazones and 1,10-phenanthroline

2020 ◽  
Vol 49 (16) ◽  
pp. 5264-5275 ◽  
Author(s):  
Débora E. S. Silva ◽  
Amanda B. Becceneri ◽  
Mariana C. Solcia ◽  
João V. B. Santiago ◽  
Mariete B. Moreira ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Induced Apoptosis ◽  
Apoptotic Effects

Ag(i) complexes induced apoptosis in triple negative breast cancer cells and were appreciably less cytotoxic against non-tumor cells.

scholarly journals S100A10 has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis.

2020 ◽  
Author(s):  
Alamelu G Bharadwaj ◽  
Margaret L Dahn ◽  
Ron-Zong Liu ◽  
Patricia Colp ◽  
Lynn N Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Invasive Carcinoma ◽  
Human Breast ◽  
Tumor Growth And Metastasis

Abstract Background: Breast cancer is one of the leading causes of cancer deaths in women worldwide. Significant advances have been made in the diagnosis and treatment of breast cancer, treatment of triple-negative and metastatic breast cancer poses significant challenge. Metastasis is a multi-step cascade that involves activation of proteases such as plasmin to facilitate the invasive escape of tumor cells to distant organs. The rate-limiting step in plasmin generation requires the interaction of plasminogen with cell surface plasminogen binding sites. Our laboratory first demonstrated that the plasminogen receptor, S100A10 (p11) was upregulated in many cancer cells and was responsible for much of their plasmin generation. Recently, it was reported that p11 is one of a few genes that are activated when human breast cancer cells metastasize from the primary tumor into the blood and is upregulated during the conversion of breast cancer cells to invasive phenotype. In the current study we have investigated the role of p11 in breast cancer tumor progression.Methods: We have used MMTV-PyMT a mouse transgenic mammary tumor model to investigate the effects of loss of p11 on spontaneous tumor initiation, growth and progression to invasive carcinoma and metastasis. We used experimental metastasis assays to ascertain the role of stromal p11 in tumor cell extravasation and lung colonization. Genes and cytokines regulated by p11 in the PyMT tumors were assessed by microarray analysis and RT-qPCR. Finally, we employed gene profiling analysis and immunohistochemical staining of breast cancer patient tumors to correlate p11 expression to human breast cancer progression. Results: Genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, immunohistochemical analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes involved in breast cancer development, progression, and inflammation such as AREG, MUC1 and S100A8. The PyMT/p11- KO tumors displayed a remarkable increase in inflammatory cytokines such as IL-6, IL-10 and IFN-γ. Gene expression profiling from 176 primary breast cancer samples obtained through the CBCF tumor bank showed that p11 mRNA levels were significantly higher in tumors compared to normal tissues. P11 mRNA expression was significantly associated with poor patient prognosis (hazard ratio – 3.34) and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. Evaluation of p11 protein expression in a NSHA cohort of patients revealed substantial upregulation of p11 in cancer tissues compared to normal controls. Conclusions: This is the first study demonstrating the crucial role of p11 in breast tumor development and metastasis. The results emphasize the potential of p11 as a diagnostic and prognostic biomarker in breast cancer.

scholarly journals Restricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells

2003 ◽  
Vol 105 (1) ◽  
pp. 7-13 ◽  
Author(s):  
Christèle Bisson ◽  
Silvia Blacher ◽  
Myriam Polette ◽  
Jean-Frédéric Blanc ◽  
Florence Kebers ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Matrix Metalloproteinase ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Membrane Type
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