miRNAs and Target Genes in Breast Cancer Metastasis

Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development.

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4543 Glucocorticoid Receptors are essential effectors of TGFβ signaling in Triple Negative Breast Cancer

Journal of Clinical and Translational Science ◽

10.1017/cts.2020.68 ◽

2020 ◽

Vol 4 (s1) ◽

pp. 7-8

Author(s):

Carlos Jesus Perez Kerkvliet ◽

Amy R Dwyer ◽

Caroline Diep ◽

Robert Oakley ◽

Christopher Liddle ◽

...

Keyword(s):

Breast Cancer ◽

P38 Mapk ◽

Cell Biology ◽

Glucocorticoid Receptors ◽

Cancer Metastasis ◽

Target Genes ◽

Mapk Signaling ◽

Breast Cancer Metastasis ◽

Tnbc Cell

OBJECTIVES/GOALS: The glucocorticoid receptor (GR) is a ubiquitous steroid hormone receptor that is emerging as a mediator of breast cancer metastasis. We aim to better understand the biology associated with phospho-GR species in TNBC and their contribution to tumor progression. METHODS/STUDY POPULATION: To better understand how p-S134 GR may impact TNBC cell biology, we probed GR regulation by soluble factors that are rich within the tumor microenvironment (TME), such as TGFβ. TNBC cells harboring endogenous wild-type or S134A-GR species were created by CRISPR/Cas knock-in and subjected to in vitro assays of advanced cancer behavior. RNA-Seq was employed to identify pS134-GR target genes that are uniquely regulated by TGFβ in the absence of exogenously added GR ligands. Direct regulation of selected TGFβ-induced pS134-GR target genes was validated accordingly. Bioinformatics tools were used to probe publicly available TNBC patient data sets for expression of a pS134-GR 24-gene signature. RESULTS/ANTICIPATED RESULTS: In the absence of GR ligands, GR is transcriptionally activated via p38-MAPK-dependent phosphorylation of Ser134 upon exposure of TNBC cells to TME-derived agents (TGFβ, HGF). The ligand-independent pS134-GR transcriptome primarily encompasses gene sets associated with TNBC cell survival and migration/invasion. Accordingly, pS134-GR was essential for TGFβ-induced TNBC cell migration, anchorage-independent growth in soft-agar, and tumorsphere formation, an in vitro readout of breast cancer stemness properties. Finally, a 24-gene pSer134-GR-dependent signature induced by TGFβ1 predicts shortened survival in breast cancer. We expect to find similar results using an in-house tissue microarray. DISCUSSION/SIGNIFICANCE OF IMPACT: Phospho-S134-GR is a critical downstream mediator of p38 MAPK signaling and TNBC migration, survival, and stemness properties. Our studies define GR as a required effector of TGFβ1 signaling and nominate pS134-GR as a biomarker of elevated risk of breast cancer dissemination.

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E3 Ubiquitin Ligase NEDD4L Negatively Regulates Breast Cancer Metastasis By Downregulating SNAI2

10.21203/rs.3.rs-956231/v1 ◽

2021 ◽

Author(s):

Baile Zuo ◽

Ying Lan ◽

Xiaoyan Li ◽

Liping Zhao ◽

Kexin Yu ◽

...

Keyword(s):

Breast Cancer ◽

Ubiquitin Ligase ◽

Prognostic Model ◽

Cancer Metastasis ◽

Target Genes ◽

Cox Regression ◽

E3 Ubiquitin Ligase ◽

Enrichment Analysis ◽

Breast Cancer Metastasis ◽

Independent Predictive Factor

Abstract Background Accumulating evidence demonstrated that the abnormal expression of E3-ubiquitin ligase NEDD4L plays an important role in the biological process of carcinomas. However, its role in breast cancer (BRCA) remains elusive. Methods The expression of NEDD4L was analyzed using BRCA datasets from public database. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for enrichment analysis. Both transwell assay and pulmonary metastasis model of BRCA were used to detect metastatic ability of cells. Western blotting, immunohistochemistry and immunofluorescence assay were used to detect the protein expression of target genes. The riskScore and nomogram were used to evaluate the prognosis of patients. Results NEDD4L was significantly downregulated in cancer tissues and positively correlated with the overall survival of patients. Knocking down NEDD4L could enhance the migration and metastasis ability of BRCA cells. SP1 promotes NEDD4L expression, resulting in SNAI2 downregulation in BRCA. A NEDD4L related to the prognostic model developed by LASSO Cox regression could be an independent predictive factor for BRCA. A nomogram combining riskScore and clinical indicators was established to evaluate the prognosis of BRCA quantitatively. Conclusions This study first reveals the role of the SP1/NEDD4L/SNAI2 axis in BRCA and establishes a reliable prognostic model, which provides a novel target and basis for clinical treatment and prognosis evaluation of breast cancer.

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Introduction: Role of miRNAs and Their Target Genes in Breast Cancer Metastasis

miRNAs and Target Genes in Breast Cancer Metastasis ◽

10.1007/978-3-319-08162-5_1 ◽

2014 ◽

pp. 1-6

Author(s):

Seema Sethi ◽

Shadan Ali ◽

Fazlul H. Sarkar

Keyword(s):

Breast Cancer ◽

Cancer Metastasis ◽

Target Genes ◽

Breast Cancer Metastasis

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E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration

10.1101/671149 ◽

2019 ◽

Author(s):

Daniel P. Hollern ◽

Matthew R. Swiatnicki ◽

Jonathan P. Rennhack ◽

Sean A. Misek ◽

Brooke C. Matson ◽

...

Keyword(s):

Breast Cancer ◽

Cell Migration ◽

Pulmonary Metastasis ◽

Target Gene ◽

Cancer Metastasis ◽

Target Genes ◽

Cancer Cell Line ◽

Breast Cancer Metastasis ◽

E2f Transcription Factors

ABSTRACTIn prior work we demonstrated that loss of E2F transcription factors inhibits metastasis. Here we address the mechanisms for this phenotype and identify the E2F regulated genes that coordinate tumor cell metastasis. Transcriptomic profiling of E2F1 knockout tumors identified a role for E2F1 as a master regulator of a suite of pro-metastatic genes, but also uncovered E2F1 target genes with an unknown role in pulmonary metastasis. High expression of one of these genes, Fgf13, is associated with early human breast cancer metastasis in a clinical dataset. Together these data led to the hypothesis that Fgf13 is critical for breast cancer metastasis, and that upregulation of Fgf13 may partially explain how E2F1 promotes breast cancer metastasis. To test this hypothesis we ablated Fgf13 via CRISPR. Deletion of Fgf13 in a MMTV-PyMT breast cancer cell line reduces the frequency of pulmonary metastasis. In addition, loss of Fgf13 reduced in vitro cell migration, suggesting that Fgf13 may be critical for tumor cells to invade out of and escape the primary tumor. The significance of this work is twofold: we have both uncovered genomic features by which E2F1 regulates metastasis and we have identified new pro-metastatic functions for the E2F1 target gene Fgf13.

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