scholarly journals Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2641
Author(s):  
Aparna Maiti ◽  
Ichiro Okano ◽  
Masanori Oshi ◽  
Maiko Okano ◽  
Wanqing Tian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Metastatic Tumor ◽  
Breast Tumors ◽  
Metastatic Lesion ◽  
Breast Cancer Metastasis ◽  
Sequencing Data ◽  
Altered Expression ◽  
Metastatic Variant

Heterogeneity is the characteristic of breast tumors, making it difficult to understand the molecular mechanism. Alteration of gene expression in the primary tumor versus the metastatic lesion remains challenging for getting any specific targeted therapy. To better understand how gene expression profile changes during metastasis, we compare the primary tumor and distant metastatic tumor gene expression using primary breast tumors compared with its metastatic variant in animal models. Our RNA sequencing data from cells revealed that parental cell and the metastatic variant cell are different in gene expression while gene signature significantly altered during metastasis to distant organs than primary breast tumors. We found that secreted mediators encoding genes (ANGPTL7, MMP3, LCN2, S100A8, and ESM1) are correlated with poor prognosis in the clinical setting as divulged from METABRIC and TCGA-BRCA cohort data analysis.

scholarly journals Metastasis-specific gene expression in autochthonous and allograft mouse mammary tumor models: stratification and identification of targetable signatures

2019 ◽  
Author(s):  
Christina Ross ◽  
Karol Szczepanek ◽  
Maxwell lee ◽  
Howard Yang ◽  
Cody J. Peer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Line ◽  
Mouse Models ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Specific Gene ◽  
Tail Vein ◽  
Specific Gene Expression

AbstractBreast cancer is a leading cause of cancer-related death of women in the U.S., which is ultimately due to metastasis rather than primary tumor burden. Therefore, increased understanding of metastasis to develop novel therapies is critical in reducing breast cancer-related mortality. Indeed, a major hurdle in advancing metastasis-targeted intervention is the genotypic and phenotypic heterogeneity that exists between primary and secondary lesions. To identify targetable metastasis-specific gene expression profiles we performed RNA sequencing of breast cancer metastasis mouse models. We analyzed metastases from models of various oncogenic drivers and routes, including orthotopic injection, tail vein injection, intracardiac injection, and genetically engineered mouse models (GEMMs). Herein, we analyzed samples from 176 mice and tissue culture samples, resulting in 338 samples total. Using these data, we contrasted the different breast cancer metastasis models, and also identified common, targetable metastasis specific gene expression signatures.Principal component analysis revealed that mouse model (Allograft v. GEMM) rather than tissue source (PT v metastatic nodule) shaped the transcriptomes of our samples. Allograft models exhibited more mesenchymal-like gene expression than GEMM models, and primary culturing of GEMM-derived metastatic tissue induced more mesenchymal-like gene expression. Furthermore, metastasis-specific gene expression differed between tail vein and orthotopic injection models of the same cell line, the degree of which was cell line dependent. Finally, we examined metastasis-specific gene expression common to models of spontaneous metastasis (orthotopic injection and GEMMs). Pathway analysis identified upregulation of the sildenafil response, and nicotine degradation pathways. The influence of these pathways on metastatic spread was assessed by treatment of allograft models with clinically relevant dosing of sildenafil or nicotine. Sildenafil significantly reduced pulmonary metastasis while nicotine administration significantly increased metastasis, and neither regimen altered primary tumor mass. Taken together our data reveals critical differences between pre-clinical models of metastatic breast cancer. Additionally, this strategy has identified clinically targetable metastasis-specific pathways integral to metastatic spread.

scholarly journals Altered Expression of Secreted Mediator Genes That Mediate Aggressive Breast Cancer Metastasis to Distant Organs

2020 ◽  
Author(s):  
Aparna Maiti ◽  
Ichiro Okano ◽  
Masanori Oshi ◽  
Maiko Okano ◽  
Wanqing Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
Primary Tumors ◽  
Altered Expression ◽  
Individual Gene ◽  
Metastatic Sites ◽  
Encoding Genes

Abstract Breast cancer most often recurs and metastasizes to the distal organs with their primary tumors surgically excised. Due to the heterogeneous nature of breast cancer, metastasis organotropism has poorly understood. This study assessed the specific cancer-related gene expression changes occurring with metastatic breast cancer recurrence to distant organs compared with non-metastatic breast cancer. We found that secreted mediators encoding genes (ANGPTL7, MMP3, LCN2, S100A8, and ESM1) are upregulated in primary breast tumors of 4T1.2, a highly metastatic variant of mouse triple-negative breast cancer (TNBC) 4T1 cells. Those genes are variably expressed at distant metastatic sites such as the spine, bone, and the lung in the syngeneic implantation/tumor-resection metastasis mouse model. The altered expression score of an individual gene was strongly associated with the survival of breast cancer patients. Notably, LCN2 and S100A8 overexpressed at the distant metastatic site spine (LCN2, 5 fold; S100A8, 6 fold) and bone (LCN2, 5 fold; S100A8, 3 fold) vs. primary tumors. In contrast, the ESM-1 encoding gene is overexpressed in the primary tumors and markedly downregulated at distant metastatic sites such as the spine, bone, and the lung. LCN2, S100A8, and ESM-1 mediators encoding individual gene expression scores were strongly associated with disease-specific survival (DSS) in the METABRIC cohort (hazard ratio [HR]>1, p < 0.0004). The gene expression scores predicted worse clinically aggressive tumors, such as high Nottingham histological grade and advanced cancer staging. High gene expression score of ESM-1 gene was strongly associated with worse overall survival (OS) in the triple-negative breast cancer (TNBC) and hormonal receptor (HR)-positive/Her2-negative subtype in METABRIC cohort, HER2+ subtype in TCGA-BRCA and SCAN-B breast cancer cohorts.Our data suggested that mediators encoding genes with both prognostic and predictive values may, therefore, be clinically useful for breast cancer spine, bone, and lung metastasis in particularly in more aggressive subtypes such as TNBC or HER2+ breast cancer.

scholarly journals Cooperation of Cancer Stem Cell Properties and Epithelial-Mesenchymal Transition in the Establishment of Breast Cancer Metastasis

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Tetsu Hayashida ◽  
Hiromitsu Jinno ◽  
Yuko Kitagawa ◽  
Masaki Kitajima
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Tumor ◽  
Breast Cancer Metastasis ◽  
Cell Junctions ◽  
Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon.

scholarly journals The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1909
Author(s):  
Tatiana S. Gerashchenko ◽  
Sofia Y. Zolotaryova ◽  
Artem M. Kiselev ◽  
Liubov A. Tashireva ◽  
Nikita M. Novikov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Ether Lipid ◽  
Metastatic Tumor ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Invasive Component ◽  
Positive Expression

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

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