Identification of Potential Long Non-Coding RNA Candidates That Contribute to Triple-Negative Breast Cancer in Humans through Computational Approach

Breast cancer (BC) is the most frequent malignancy identified in adult females, resulting in enormous financial losses worldwide. Owing to the heterogeneity as well as various molecular subtypes, the molecular pathways underlying carcinogenesis in various forms of BC are distinct. Therefore, the advancement of alternative therapy is required to combat the ailment. Recent analyses propose that long non-coding RNAs (lncRNAs) perform an essential function in controlling immune response, and therefore, may provide essential information about the disorder. However, their function in patients with triple-negative BC (TNBC) has not been explored in detail. Here, we analyzed the changes in the genomic expression of messenger RNA (mRNA) and lncRNA in standard control in response to cancer metastasis using publicly available single-cell RNA-Seq data. We identified a total of 197 potentially novel lncRNAs in TNBC patients of which 86 were differentially upregulated and 111 were differentially downregulated. In addition, among the 909 candidate lncRNA transcripts, 19 were significantly differentially expressed (DE) of which three were upregulated and 16 were downregulated. On the other hand, 1901 mRNA transcripts were significantly DE of which 1110 were upregulated and 791 were downregulated by TNBCs subtypes. The Gene Ontology (GO) analyses showed that some of the host genes were enriched in various biological, molecular, and cellular functions. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis showed that some of the genes were involved in only one pathway of prostate cancer. The lncRNA-miRNA-gene network analysis showed that the lncRNAs TCONS_00076394 and TCONS_00051377 interacted with breast cancer-related micro RNAs (miRNAs) and the host genes of these lncRNAs were also functionally related to breast cancer. Thus, this study provides novel lncRNAs as potential biomarkers for the therapeutic intervention of this cancer subtype.

Download Full-text

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

Download Full-text

Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells

Molecules ◽

10.3390/molecules26123644 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3644

Author(s):

Daeun You ◽

Yisun Jeong ◽

Sun Young Yoon ◽

Sung A Kim ◽

Eunji Lo ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Lung Metastasis ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Interleukin 1 ◽

Metastatic Potential ◽

Cancer Cell Proliferation ◽

Dependent Pathway

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

Download Full-text

Repositioning metformin and propranolol for colorectal and triple negative breast cancers treatment

Scientific Reports ◽

10.1038/s41598-021-87525-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

L. E. Anselmino ◽

M. V. Baglioni ◽

F. Malizia ◽

N. Cesatti Laluce ◽

C. Borini Etichetti ◽

...

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Triple Negative ◽

Epithelial Mesenchymal Transition ◽

Drug Repositioning ◽

Combined Treatment ◽

Alternative Therapy ◽

Breast Cancers ◽

Mesenchymal Transition ◽

Tumor Types

AbstractDrug repositioning refers to new uses for existing drugs outside the scope of the original medical indications. This approach fastens the process of drug development allowing finding effective drugs with reduced side effects and lower costs. Colorectal cancer (CRC) is often diagnosed at advanced stages, when the probability of chemotherapy resistance is higher. Triple negative breast cancer (TNBC) is the most aggressive type of breast cancer, highly metastatic and difficult to treat. For both tumor types, available treatments are generally associated to severe side effects. In our work, we explored the effect of combining metformin and propranolol, two repositioned drugs, in both tumor types. We demonstrate that treatment affects viability, epithelial-mesenchymal transition and migratory potential of CRC cells as we described before for TNBC. We show that combined treatment affects different steps leading to metastasis in TNBC. Moreover, combined treatment is also effective preventing the development of 5-FU resistant CRC. Our data suggest that combination of metformin and propranolol could be useful as a putative adjuvant treatment for both TNBC and CRC and an alternative for chemo-resistant CRC, providing a low-cost alternative therapy without associated toxicity.

Download Full-text

CPSF4 promotes triple negative breast cancer metastasis by upregulating MDM4

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00565-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Kaping Lee ◽

Qiufan Zheng ◽

Qianyi Lu ◽

Fei Xu ◽

Ge Qin ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis

Download Full-text

Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer

10.1101/2020.09.11.293837 ◽

2020 ◽

Author(s):

Suzann Duan ◽

Senny Nordmeier ◽

Aidan E. Byrnes ◽

Iain L. O. Buxton

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Endothelial Cell ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Purinergic Signaling ◽

Endothelial Cell Migration ◽

Metastatic Niche ◽

Niche Formation

AbstractMetastasis accounts for over 90% of cancer-related deaths. The mechanisms guiding this process remain unclear. Secreted nucleoside diphosphate kinase A and B (NDPK) support breast cancer metastasis. Proteomic evidence confirms their presence in breast cancer-derived extracellular vesicles (EVs). We investigated the role of EV-associated NDPK in modulating the host microenvironment in favor of pre-metastatic niche formation. We measured NDPK expression and activity in EVs isolated from triple-negative breast cancer (MDA-MB-231) and non-tumorigenic mammary epithelial (HME1) cells using flow cytometry, western blot, and ATP assay. We evaluated the effects of EV-associated NDPK on endothelial cell migration, vascular remodeling, and metastasis. We further assessed MDA-MB-231 EV induced-proteomic changes in support of pre-metastatic lung niche formation. NDPK-B expression and phosphotransferase activity were enriched in MDA-MB-231 EVs that promote vascular endothelial cell migration and disrupt monolayer integrity. MDA-MB-231 EV-treated mice demonstrate pulmonary vascular leakage and enhanced experimental lung metastasis, whereas treatment with an NDPK inhibitor or a P2Y1 purinoreceptor antagonist blunts these effects. We identified perturbations to the purinergic signaling pathway in experimental lungs, lending evidence to support a role for EV-associated NDPK-B in lung pre-metastatic niche formation and metastatic outgrowth.

Download Full-text

S-nitrosylation of CYR61 protein reduces triple-negative breast cancer metastasis ability

10.21203/rs.3.rs-86057/v1 ◽

2020 ◽

Author(s):

Lee Jia ◽

Yusheng Lu ◽

Sudan He ◽

Huanzhang Xie ◽

Chunlian Zhong ◽

...

Keyword(s):

Breast Cancer ◽

Mass Spectrometry ◽

Intravenous Injection ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

3D Structure ◽

Protein S ◽

Adhesion Assay ◽

Biotin Switch

Abstract BackgroundTriple-negative breast cancer (TNBC) is the most difficult cancer to be treated. TNBC expresses high level of matricellular cysteine-rich protein CYR61/CCN1 that plays a key role in producing cancer metastases and is an important target for metastasis chemoprevention. Nitric oxide (NO) can covalently bind to the thiol group of cysteines (termed S-nitrosylation) resulting in regulation of the targeted protein functions. MethodsProtein S-nitrosylation were detected by biotin-switch assay and western blotting assay. CYR61 protein S-nitrosylated sites and 3D structure were determined by mass spectrometry and MODELLER software. Adhesion assay, cell morphology assay, wound healing assay and transwell invasion assay were used to evaluate effects of CYR61 S-nitrosylation on the cell metastatic ability. In vivo metastasis activity of CYR61 S-nitrosylation were tested by intravenous injection and mammary xenograft implantation mouse metastatic models.ResultsS-nitrosylation by GSNO of CYR61 reached a plateau quickly and was confirmed by spectroscopic analysis and biotin-switch assay. Mass-spectrometry proteomic analysis revealed that S-nitrosylation predominantly occurred at Cys100, Cys117, Cys229 and Cys239, resulting in CYR61 structure relaxed and unstable evidenced by protein structure modeling. S-nitrosylation of MDA-MB-231 cells, their CYR61-overexpressed and CYR61–silenced counterparts significantly attenuated the metastatic ability of these cells, including their ability of adhesion, mobility, invasion, and interplay with platelets, and made the adhered cells unattached. The attenuation in metastatic ability proportionally increased with the degree of S-nitrosylation to CYR61 naturally-expressed or genetically-manipulated cells, and was demonstrated in mice, where, S-nitrosylation of these cell lines not only inhibited their acute seeding to lungs after an intravenous injection, but also inhibited the late development of these cells into the metastatic nodes after mammary xenograft implantation. Furthermore, orthotopically-implanted MDA-MB-231 developed mammary tumors and later lung metastasis; whereas, the same cells with S-nitrosylation developed no tumor and metastasis at all. Conclusionwe present the first evidence that S-nitrosylation of CYR61 can significantly inhibit metastatic aggressiveness of the TNBC MDA-MB-231 cells. This conceptual creative study opens a new avenue to prevent the most aggressive TNBC from metastases by S-nitrosylation to CYR61.

Download Full-text

Autophagy promotes triple negative breast cancer metastasis via YAP nuclear localization

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2019.09.133 ◽

2019 ◽

Vol 520 (2) ◽

pp. 263-268 ◽

Cited By ~ 9

Author(s):

Wei Chen ◽

Yuxin Bai ◽

Chrishma Patel ◽

Fei Geng

Keyword(s):

Breast Cancer ◽

Nuclear Localization ◽

Triple Negative Breast Cancer ◽

Cancer Metastasis ◽

Triple Negative ◽

Breast Cancer Metastasis

Download Full-text

The CXCR4-Dependent LASP1-Ago2 Interaction in Triple-Negative Breast Cancer

Cancers ◽

10.3390/cancers12092455 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2455

Author(s):

Augustus M. C. Tilley ◽

Cory M. Howard ◽

Sangita Sridharan ◽

Boopathi Subramaniyan ◽

Nicole R. Bearss ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Chemokine Receptor ◽

Cancer Metastasis ◽

Triple Negative ◽

Receptor Type ◽

Proximity Ligation Assay ◽

Dependent Manner ◽

Invasive Ability ◽

Matrigel Invasion

The CXCR4-LASP1 axis is an emerging target in the field of breast cancer metastasis. C-X-C chemokine receptor type 4 (CXCR4) mediates directed cell migration when activated by its cognate ligand CXCL12. LIM and SH3 Protein 1 (LASP1) is a critical node in the CXCR4 signaling pathway, as its deficiency blocks CXCR4-dependent Matrigel invasion. The mechanism by which LASP1 facilitates this invasive ability of tumor cells when CXCR4 is activated is unknown. Our previous proteomics work had revealed several components of the RNA interference (RNAi) machinery as being potential LASP1 interacting proteins. Here we report that argonaute 2 (Ago2), a protein with central involvement in RNAi, associates with LASP1 in triple-negative breast cancer (TNBC) cells. We demonstrate that LASP1 co-immunoprecipitates with Ago2 endogenously in a CXCL12-dependent manner, with further confirmation of this interaction by proximity ligation assay. Furthermore, this association is specific to CXCR4 as it can be abrogated by the CXCR4 antagonist, AMD3465. By GST-pulldown approach, we identify that LASP1 directly binds to Ago2 through its LIM and SH3 domains, and that this binding is dictated by the S146 and Y171 phosphorylation sites of LASP1. Additionally, the phosphorylation status of LASP1 affected tumor suppressor microRNA (miRNA) Let-7a-guided Ago2 activity. Levels of several endogenous targets of Let-7a were found to be altered including C-C chemokine receptor type 7 (CCR7), which is another critical chemokine receptor involved in metastasis to lymph nodes. Our results suggest a novel role for the LASP1-Ago2 module in shaping the RNAi landscape, functionally impacting the invasive ability of cancer cells.

Download Full-text