Cell Migration as a Therapeutic Target in Malignant Breast Cancer

2000 ◽  
Author(s):  
George E. Plopper ◽  
Jr
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Therapeutic Target ◽  
Malignant Breast

scholarly journals Bcl-3 promotes multi-modal tumour cell migration via NF-κB1 mediated regulation of Cdc42

2020 ◽  
Vol 41 (10) ◽  
pp. 1432-1443 ◽  
Author(s):  
Daniel J Turnham ◽  
William W Yang ◽  
Julia Davies ◽  
Athina Varnava ◽  
Anne J Ridley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Therapeutic Target ◽  
Breast Cancer Cells ◽  
Metastatic Tumour ◽  
Tumour Burden

Abstract A key challenge in the implementation of anti-metastatics as cancer therapies is the multi-modal nature of cell migration, which allows tumour cells to evade the targeted inhibition of specific cell motility pathways. The nuclear factor-kappaB (NF-κB) co-factor B-cell lymphoma 3 (Bcl-3) has been implicated in breast cancer cell migration and metastasis, yet it remains to be determined exactly which cell motility pathways are controlled by Bcl-3 and whether migrating tumour cells are able to evade Bcl-3 intervention. Addressing these questions and the mechanism underpinning Bcl-3’s role in this process would help determine its potential as a therapeutic target. Here we identify Bcl-3 as an upstream regulator of the two principal forms of breast cancer cell motility, involving collective and single-cell migration. This was found to be mediated by the master regulator Cdc42 through binding of the NF-κB transcription factor p50 to the Cdc42 promoter. Notably, Bcl-3 depletion inhibited both stable and transitory motility phenotypes in breast cancer cells with no evidence of migratory adaptation. Overexpression of Bcl-3 enhanced migration and increased metastatic tumour burden of breast cancer cells in vivo, whereas overexpression of a mutant Bcl-3 protein, which is unable to bind p50, suppressed cell migration and metastatic tumour burden suggesting that disruption of Bcl-3/NF-κB complexes is sufficient to inhibit metastasis. These findings identify a novel role for Bcl-3 in intrinsic and adaptive multi-modal cell migration mediated by its direct regulation of the Rho GTPase Cdc42 and identify the upstream Bcl-3:p50 transcription complex as a potential therapeutic target for metastatic disease.

scholarly journals SEPT9_i1 regulates human breast cancer cell motility through cytoskeletal and RhoA/FAK signaling pathway regulation

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Yongqiu Zeng ◽  
Yang Cao ◽  
Lan Liu ◽  
Jiao Zhao ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Focal Adhesion ◽  
Therapeutic Target ◽  
Lung Metastases ◽  
Cytoskeletal Proteins ◽  
Tumor Cell Migration ◽  
Mcf 7

Abstract Increasing cell mobility is the basis of tumor invasion and metastasis, and is therefore a therapeutic target for preventing the spread of many types of cancer. Septins are a family of cytoskeletal proteins with GTPase activity, and play a role in many important cellular functions, including cell migration. SEPT9 isoform 1 protein (SEPT9_i1) has been associated with breast tumor development and the enhancement of cell migration; however, the exact mechanism of how SEPT9_i1 might affect breast cancer progression remains to be elucidated. Here, we report that the expression of SEPT9_i1 positively correlated with paxillin, and both were significantly upregulated in invasive breast cancer tissues of patients with lymph node metastases. Lentivirus-mediated shRNA knockdown of SEPT9 in MCF-7 cells diminished tumor cell migration, focal adhesion (FA) maturation and the expression of β-actin, β-tubulin, Cdc42, RhoA, and Rac, whereas overexpression of SEPT9_i1 in SEPT9-knockdown MCF-7 cells promoted cell migration, FA maturation and relevant protein expression. Furthermore, overexpression of SEPT9_i1 in MCF-7 cells markedly increased FAK/Src/paxillin signaling, at least in part through RhoA/ROCK1 upstream activation. Transcriptome profiling suggested that SEPT9_i1 may directly affect “Focal adhesion” and “Regulation of actin cytoskeleton” signaling mechanisms. Finally, overexpression of SEPT9_i1 markedly enhanced lung metastases in vivo 6 weeks after tumor inoculation. These findings suggest that a mechanism of Septin-9-induced aberrant cancer cell migration is through cytoskeletal regulation and FA modulation, and encourages the use of SEPT9 as novel therapeutic target in the prevention of tumor metastasis.

scholarly journals Mammaglobin A as a diagnostic marker and therapeutic target in breast cancer

2020 ◽  
Vol 74 ◽  
pp. 566-571
Author(s):  
Natalia Lisiak ◽  
Maria Sierszulska ◽  
Julia Bajsert
Keyword(s):  
Breast Cancer ◽  
Therapeutic Target ◽  
Diagnostic Marker ◽  
Correct Diagnosis ◽  
High Sensitivity ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Diagnosis And Prognosis ◽  
Promising Tool ◽  
Malignant Breast

Breast cancer is the most frequently diagnosed malignant tumor in women. Due to the high heterogeneity and multiplicity of histological subtypes within this type of cancer, the expression of breast cancer markers is very diverse. Therefore, a biomarker with high sensitivity and specificity would be extremely important for the correct diagnosis and prognosis assessment in breast cancer patients. Mammaglobin A seems to be such a biomarker. Overexpression of this protein is closely related with carcinogenesis in the mammary gland and is observed in up to 80% of cases of the malignant breast cancers. According to many reports, it is postulated that mammaglobin A may be a promising tool in the diagnostics of cancers but also a prognostic, predictive and therapeutic factor. The information contained in this publication presents the current state of knowledge about the structure of mammaglobin A, its function, role in the tumorigenesis and the use of this protein as a diagnostic marker and therapeutic target in breast cancer.

scholarly journals Ethanol Extracts of Dietary Herb, Alpinia nantoensis, Exhibit Anticancer Potential in Human Breast Cancer Cells

2019 ◽  
Vol 18 ◽  
pp. 153473541986692 ◽  
Author(s):  
Ching-Ying Kuo ◽  
Teng-Song Weng ◽  
K. J. Senthil Kumar ◽  
Yen-Hsueh Tseng ◽  
Ta-Wei Tung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Leaf Extracts ◽  
Malignant Breast ◽  
Ethanol Extracts

Recent advances in mammography screening, chemotherapy, and adjuvant treatment modalities have improved the survival rate of women with breast cancer. Nevertheless, the breast tumor with metastatic progression is still life-threatening. Indeed, combination therapy with Ras-ERK and PI3K inhibitors is clinically effective in malignant breast cancer treatment. Constituents from genus Alpinia plants have been implicated as potent anticancer agents in terms of their efficacy of inhibiting tumor cell metastasis. In this study, we tested the effects of ethanol extracts of Alpinia nantoensis (rhizome, stem, and leaf extracts) in cultured human breast cancer cells and particularly focused on the Ras-ERK and PI3K/AKT pathways. We found that the rhizome and leaf extracts from A nantoensis inhibited cell migration, invasion, and sphere formation in MCF-7 and MDA-MB-231 cells. The potency was extended with the inhibition of serum-induced PI3K/AKT and Ras-ERK activation and epidermal growth factor (EGF)-mediated EGFR activation in MDA-MB-231 cells. These results indicate that extracts of A nantoensis could inhibit signal transduction at least involved in EGFR as well as the PI3K/AKT and Ras-ERK pathways, which are crucial players of tumor cell migration and invasion. Our study strongly supports that the extracts of A nantoensis could be a novel botanical drug lead for the development of an antimetastatic agent for the treatment of human malignant breast cancer.

scholarly journals USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Oncogenesis ◽  
2021 ◽  
Vol 10 (3) ◽  
Author(s):  
Fabiana Alejandra Rossi ◽  
Juliana Haydeé Enriqué Steinberg ◽  
Ezequiel Hernán Calvo Roitberg ◽  
Molishree Umesh Joshi ◽  
Ahwan Pandey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Therapeutic Target ◽  
Migration And Invasion ◽  
Invasive Potential ◽  
Cell Migration And Invasion ◽  
Tumor Cell Migration ◽  
Ubiquitination Pathway

AbstractTumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

scholarly journals USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

2020 ◽  
Author(s):  
Fabiana A Rossi ◽  
Juliana H Enriqué Steinberg ◽  
Ezequiel H Calvo Roitberg ◽  
Molishree Joshi ◽  
Ahwan Pandey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Therapeutic Target ◽  
Migration And Invasion ◽  
Invasive Potential ◽  
Cell Migration And Invasion ◽  
Tumor Cell Migration ◽  
Ubiquitination Pathway

ABSTRACTTumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.

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