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Gene-expression profile of triple negative breast cancer cells stimulated with post-surgery wound-healing fluids

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype showing high recurrences and mortality rate, for which no therapies besides chemotherapy are available to date. Lacking specific markers for an effective targeted therapy, TNBCs still represent the most important challenge for clinical oncologists.TNBC definition for lack of expression markers underscored the urgent need of discover the “drivers” for this disease and their role in aggressiveness to develop specific targeted therapies. In the effort to identify drivers responsible of early TNBC relapse, we choose to take advantage of the pro-tumorigenic activity of post-surgery wound healing fluids (WHFs) of breast cancer patients that represents the microenvironment constituted of peripheral blood of patients in which disseminated tumor cells reside and that can strongly influence the survival of tumor cells allowing distant relapses. . The stimulus of this enriched microenvironment created immediately post-surgery can determine a selecting pressure for the survival of most aggressive tumor cells modulating the expression of existing or new molecules on TNBC surface driving the develop of distant metastases. By using WHF to stimulate human TNBC cell models prior gene expression profile, we identify the significant up-modulation of the plasma membrane receptor CUB-domain containing protein 1 (CDCP1).

ORGANISM(S): Homo sapiens

PROVIDER: GSE59614 | GEO | 2017/06/12

SECONDARY ACCESSION(S): PRJNA255759

REPOSITORIES: GEO

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Detection and isolation of circulating tumor cells from breast cancer patients using CUB domain-containing protein 1 (CDCP1) Detection and isolation of circulating tumor cells from breast cancer patients using CUB domain-containing protein 1 (CDCP1) Detection and isolation of circulating tumor cells from breast cancer patients using CUB domain-containing protein 1 (CDCP1)

Project description:Circulating tumor cells (CTCs) and disseminated tumour cells with mesenchymal traits are difficult to detect by epithelial marker proteins. Particularly, triple negative breast cancers (TNBC) that are prone to therapy failure release a subpopulation of circulating tumour cells (CTCs) with mesenchymal traits. To provide tools that support their detection and analysis, the cell line BC-M1 established from disseminated tumour cells in the bone marrow of a breast cancer patient and a bone metastasis subline of MDA-MB-231 were analysed. Mass spectrometry analysis revealed high levels of CUB domain-containing protein 1 (CDCP1) in BC-M1. CDCP1 was found in other carcinoma cell lines (MDA-MB-231, MDA-MB-468) and other DTC cell lines (LC-M1, PC-E1) as well. Peripheral blood mononuclear cells were virtually negative for CDCP1 by Western Blot and immunofluorescent staining. Presence of CDCP1 in CTCs was confirmed by CellSearch. Here, CDCP1 positive CTCs were detected in eight of 30 analysed breast cancer patients. For the isolation of CTCs from the blood of breast cancer patients, we established a sandwich magnetic-activated cell sorting (MACS). The extracellular domain of CDCP1 served for cell catching and the cytoplasmic domain of CDCP1 for immunofluorescent detection of CDCP1 in CTCs. We showed that the MACS approach is suitable for the isolation of EpCam/keratin negative breast cancer cells from the blood and isolated CDCP1 positive CTCs from breast cancer patients by MACS. Hence, our approach is particularly suited for the detection and isolation of CTCs from TNBC when low EpCam or keratin levels limit the application of conventional approaches.

2023-03-20 | PXD035203 | Pride

USP22 supports the aggressive behavior of basal-like breast cancer by stimulating cellular respiration

Project description:Breast cancer (BC), the most frequent tumor entity in women globally, shows a high therapeutic response in early and non-metastatic stages. However, triple-negative BC (TNBC), enriched with cancer stem cells (CSCs), presents significant challenges due to its chemoresistant and metastatic nature. Ubiquitin Specific Proteinase 22 (USP22) has emerged as a key player in promoting CSC functions, contributing to resistance to conventional therapies, tumor relapse, metastasis, and poor survival across various cancers, including BC. The specific role of USP22 in TNBC, however, remains underexplored. In this study, we employed the MMTV-cre, Usp22fl/fl transgenic mouse model to investigate USP22's influence on stem cell-like properties in mammary tissue. High-throughput transcriptomic analyses, combined with publicly available patient data and TNBC culture models, were utilized to elucidate USP22's role in CSC characteristics of TNBC. Our findings reveal that USP22 enhances CSC properties and drug tolerance by supporting oxidative phosphorylation, a key factor in the poor response to conventional therapies in aggressive BC subtypes. The study uncovers a novel tumor-supportive role of USP22 in sustaining cellular respiration, which contributes to the drug-tolerant behavior of HER2+-BC and TNBC cells. This highlights USP22 as a potential therapeutic target, offering new avenues to optimize standard treatments and address the aggressiveness of these malignancies.

2023-12-31 | E-MTAB-13577 | biostudies-arrayexpress

Expression data of patient-derived triple negative breast cancer xenograft tumors

Project description:Triple negative breast cancer (TNBC) is an aggressive subtype that lack targeted clinical therapies. In addition, TNBC is heterogeneous and was recently further sub-classified into seven TNBC subtypes that displayed unique gene expression patterns. To develop therapeutic treatment regimens, we established seven patient-derived xenograft models from TNBC tumors. These xenograft models not only retained the histology and clinical markers of the corresponding patient tumors, but also bearing the same mutations and deletions identified in the patient tumors. Moreover, as part of evaluation of these models, we performed microarrays on the xenograft tumors to assess their TNBC subtypes. After obtaining IRB-approved informed written patient consent, breast cancer tissues were obtained fresh from Stanford Hospital and transplanted into the number 2 mammary fat pads of female NOD SCID mice (NOD.CB17-Prkdcscid/J, Jackson Laboratory West, Sacramento, CA, USA). Mice were maintained in pathogen-free animal housing. The established xenografts were subsequently passaged from mouse to mouse. Xenograft tumor tissues were frozen on dry ice for RNA isolation and microarray analysis.

2014-03-21 | E-GEOD-47079 | biostudies-arrayexpress

Comprehensive proteomic characterization reveals subclass-specific molecular aberrations within triple-negative breast cancer

Project description:Triple-negative breast cancer (TNBC) is regarded as the most aggressive subtype of breast cancer lacking targeted therapies. This is attributed to its high heterogeneity that complicates elucidation of its molecular aberrations. Here, we report identification of specific proteome expression profiles pertaining to two TNBC subclasses, basal A and basal B, through in-depth proteomics analysis of breast cancer cells. We observed that kinases and proteases displayed unique expression patterns within the subclasses, similar to whole proteome clusters. Systematic analyses of protein-protein interaction and co-regulation networks of these kinases and proteases unraveled dysregulated pathways and plausible targets for each TNBC subclass. Among these, we identified kinases AXL, PEAK1 and TGFBR2, and proteases FAP, UCHL1 and MMP2/14, as specific targets for basal B subclass, which represents the more aggressive TNBC cell lines. Our study thus highlights intricate mechanisms and distinct targets within TNBC, and emphasizes that these have to be exploited in a subclass-specific manner rather than a one-for-all TNBC therapy.

2020-03-03 | PXD017025 | Pride

Marizomib eradicates primary and metastatic triple-negative breast cancer via proteasome and oxidative phosphorylation inhibition

Project description:Lacking effective targeted therapies, triple-negative breast cancer (TNBCs) is highly aggressive, metastatic, and clinically challenging breast cancer subtype with worst prognosis. Despite survival dependency on the proteasome pathway genes, the FDA-approved proteasome inhibitors induced minimal clinical response in TNBC patients due to weaker proteasome inhibition. Here, we show that a novel proteasome inhibitor Marizomib (Mzb), inhibited multiple proteasome catalytic activities and induced better anti-tumor response in TNBC cell line and patient-derived xenografts alone and in combination with a standard-of-care chemotherapy, doxorubicin. Mechanistically, Mzb inhibits oxidative phosphorylation (OXPHOS) via PGC-1α suppression in conjunction with proteasome inhibition in TNBC cells. Development of metastatic disease, especially brain metastasis, remains a reason for a greater mortality rate amongst TNBC patients. Mzb reduces lung and brain metastasis in vivo by reducing circulating tumor cells and the expression of multiple epithelial-to-mesenchymal genes. We also demonstrate that Mzb-induced OXPHOS inhibition upregulates glycolysis to fulfill the metabolic demand of TNBC cells and hence, combined inhibition of glycolysis with Mzb leads to a synergistic anti-cancer activity in vivo. Collectively, our data provide a strong rationale for the clinical evaluation of Mzb in primary and metastatic TNBC patients.

2020-05-27 | PXD015141 | Pride

Gene expression profiles of triple-negative breast cancer cells under the condition of 3D proliferation

Project description:Triple-negative breast cancer (TNBC) is defined by the absence of estrogen and progesterone receptors and human epidermal growth factor receptor 2, and is the most lethal and aggressive subtype of breast cancer. However, the genes which relate to promote tumor aggressiveness in TNBC remain unclear. In order to investigate specific genes and pathways involved in TNBC tumorigenesis, we compared genes differentially expressed between 3D cultures (3DC) or tumor xenograft models and control two-dimensional cultures (2DC). Total RNA was prepared from the TNBC cells under the condition of 2DC, 3DC and tumor xenograft models, and applied to Affymetrix Human Genome U133 Plus 2.0 Array.

2012-04-30 | E-GEOD-36953 | biostudies-arrayexpress

Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance

Project description:Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin- dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8–PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.

2021-10-21 | GSE161295 | GEO

Quantitative Pattern of hPTMs by Mass Spectrometry-based Proteomics with Implications for Triple-Negative Breast Cancer

Project description:Triple-negative breast cancer (TNBC) is characterized by its aggressive behavior, with trend to early relapse and metastasis as well as poor survival. Limited therapies and lack of effective therapeutic targets are one of the main challenges in clinical management of TNBC. Histone post-translational modifications (hPTMs) have been implicated in breast cancer. However, rare information on the association between hPTMs and molecular subtypes of breast cancer can be found so far.

2024-02-01 | PXD049101 | iProX

Proteomic analysis of triple negative mouse breast cancer isografts after electro-hyperthermia treatment

Project description:Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor, by elevated oxidative glycolysis (Warburg effect) and conductivity of the tumor. The EMF induce cell death by thermal and non-thermal effects. Here we investigated an aggressive, therapy resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT 3-5 times. mEHT induced the upregulation of the stress related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation.

2021-04-14 | PXD024150 | Pride

MicroRNA expression data from an epithelial-mesenchymal transition (EMT) model of triple negative breast cancer (TNBC).

Project description:Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer due to lack of effective targeted therapies. Here, we report that the expression of miR-4417 is suppressed during the progression of TNBC cells from non-malignant to the malignant stage. miR-4417 is localized to chromosome 1p36, a region with high loss of heterozygosity in multiple cancers, and its biogenesis is DICER-dependent. Low expression of miR-4417 is significantly associated with worse prognosis in TNBC patients, while overexpression of miR-4417 is sufficient to inhibit migration and tumorigenecity of TNBC cells in vitro. Overall, our findings suggest that miR-4417 exerts a tumor suppressive effect and thereby could serve as a prognostic biomarker and therapeutic tool against TNBC. We used microarrays to profile the global miRNA changes during EMT to identify putative tumor suppressors and prognostic biomarkers for TNBC.

2019-10-15 | GSE121657 | GEO

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