scholarly journals Dissecting RAS Oncogene-Induced Kinome Involved in Breast Cancer Metastasis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Amna Yaqub ◽  
Harikrishna Harikrishna Nakshatri2
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Kinase Inhibitor ◽  
Breast Cancer Metastasis ◽  
Model System ◽  
Transformed Cells ◽  
Normal Cells ◽  
Ras Pathway ◽  
Transformed Cell Line

Background and Hypothesis: The RAS and PI3K-AKT-mTOR signaling pathways are often dysregulated in cancer. RAS pathway alterations, however, are more common in breast cancer metastasis. The laboratory’s recently developed model system demonstrated the ability of RAS but not PIK3CA-induced signals in promoting metastasis of breast cancer. Unbiased kinome analyses of isogenic RAS-transformed primary tumor and metastatic cells and PIK3CA-transformed primary tumor cells enabled identification of RAS-activated kinome, which included FER, PAK4, LIMK1, PIK3CD and Casein Kinase 2 (CK2). We hypothesized that therapeutic targeting of these kinases may reduce breast cancer metastasis. As a proof-of-principle, the effect of the CK2 inhibitor Silmitasertib, which is in clinical trial for COVID-19 and refractory multiple myeloma, was tested. Experimental Design: The study included four isogenic cell lines: “normal” (KTB34-hTERT), PIK3CA-transformed (TKTB34-PIK3CA), RAS-transformed (TKTB34-RAS), and RAS-transformed cells metastasized to lungs (MKTB34-RAS). Active kinomes in these cells were identified using phospho-proteomics and functional kinome profiling using multiplexed kinase inhibitor beads. Expression levels of FER, PAK4, LIMK1, and PIK3CD kinases were compared through Western Blot using the phospho-antibodies as an indicator of kinase activation. Sensitivity to Silmitasertib was measured using the BrdU Cell Proliferation Assay. Results: FER, PAK4, LIMK1, and PIK3CD were all overexpressed in the TKTB34-RAS and MKTB34-RAS cells compared to KTB34-hTERT and TKTB34-PIK3CA cells. The tested concentration range for Silmitasertib (500 nM to 5 µM) was ineffective in killing the RAS-transformed cells and was overly toxic to “normal” cells. Conclusion and Potential Impact: FER, PAK4, LIMK1, PIK3CD, and CK2 are potential therapeutic targets for breast cancer metastasis. However, Silmitasertib may not be a good candidate as it is more toxic to “normal” cells compared to cancer cells. The isogenic “normal” and transformed cell line model system described here may help to discover new targets and drugs that kill cancer but not normal cells.

scholarly journals Reduction of Raf-1 Kinase Inhibitor Protein Expression Correlates with Breast Cancer Metastasis

2005 ◽  
Vol 11 (20) ◽  
pp. 7392-7397 ◽  
Author(s):  
Suzanne Hagan ◽  
Fahd Al-Mulla ◽  
Elizabeth Mallon ◽  
Karin Oien ◽  
Rhona Ferrier ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Metastasis ◽  
Kinase Inhibitor ◽  
Breast Cancer Metastasis ◽  
Inhibitor Protein

scholarly journals Aicardi-Goutières Syndrome gene Rnaseh2c is a metastasis susceptibility gene in breast cancer

2019 ◽  
Author(s):  
Sarah K. Deasy ◽  
Ryo Uehara ◽  
Suman K. Vodnala ◽  
Howard H. Yang ◽  
Randall A. Dass ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Metastatic Disease ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
The United States ◽  
Breast Cancer Metastasis ◽  
Rnase H2

AbstractBreast cancer is the second leading cause of cancer-related deaths in the United States, with the majority of these deaths due to metastatic lesions rather than the primary tumor. Thus, a better understanding of the etiology of metastatic disease is crucial for improving survival. Using a haplotype mapping strategy in mouse and shRNA-mediated gene knockdown, we identified Rnaseh2c, a scaffolding protein of the heterotrimeric RNase H2 endoribonuclease complex, as a novel metastasis susceptibility factor. We found that the role of Rnaseh2c in metastatic disease is independent of RNase H2 enzymatic activity, and immunophenotyping and RNA-sequencing analysis revealed engagement of the T cell-mediated adaptive immune response. Furthermore, the cGAS-Sting pathway was not activated in the metastatic cancer cells used in this study, suggesting that the mechanism of immune response in breast cancer is different from the mechanism proposed for Aicardi-Goutières Syndrome, a rare interferonopathy caused by RNase H2 mutation. These results suggest an important novel, non-enzymatic role for RNASEH2C during breast cancer progression and add Rnaseh2c to a panel of genes we have identified that together could determine patients with high risk for metastasis. These results also highlight a potential new target for combination with immunotherapies and may contribute to a better understanding of the etiology of Aicardi-Goutières Syndrome autoimmunity.Author SummaryThe majority of breast cancer-associated deaths are due to metastatic disease, the process where cancerous cells leave the primary tumor in the breast and spread to a new location in the body. To better understand the etiology of this process, we investigate the effects of gene expression changes in the primary tumor. In this study, we found that changing the expression of the gene Rnaseh2c changed the number of metastases that developed in the lungs of tumor-bearing mice. By investigating the enzyme complex Rnaseh2c is part of, RNase H2, we determined that Rnaseh2c’s effects may be independent of RNase H2 enzyme activity. Because Rnaseh2c is known to cause the autoimmune disease Aicardi-Goutières Syndrome (AGS), we tested whether the immune system is involved in the metastatic effect. Indeed, we found that the cytotoxic T cell response is important for mediating the effect that Rnaseh2c has on metastasis. Together these data indicate that Rnaseh2c expression contributes to a patient’s susceptibility to developing breast cancer metastasis and demonstrate that the immune system is involved in this outcome. The implications of this study suggest immunotherapy could be a viable treatment for breast cancer metastasis and may help inform the understanding of AGS and RNase H2 in cancer.

scholarly journals Phosphorylation of serine 367 of FOXC2 by p38 regulates ZEB1 and breast cancer metastasis, without impacting primary tumor growth

Oncogene ◽  
2016 ◽  
Vol 35 (46) ◽  
pp. 5977-5988 ◽  
Author(s):  
S J Werden ◽  
N Sphyris ◽  
T R Sarkar ◽  
A N Paranjape ◽  
A M LaBaff ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Primary Tumor Growth

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.

Recent Advances in Breast Cancer Metastasis Suppressor 1

2011 ◽  
Vol 26 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Xiuping Chen ◽  
Zengtao Xu ◽  
Yitao Wang
Keyword(s):  
Breast Cancer ◽  
Primary Tumor ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Tumor Formation ◽  
In Vivo Studies ◽  
Secondary Site ◽  
Metastasis Suppressor ◽  
Metastasis Suppressor 1 ◽  
Breast Cancer Metastasis Suppressor

Metastasis is a complex process divided into a number of steps including detachment of tumor cells from the primary tumor, invasion, migration, intravasation, survival in the vasculature, extravasation, and colonization of the secondary site. Proteins that block metastasis without inhibiting primary tumor formation are known as metastasis suppressors; examples are NM23, Maspin, KAI1, KISS1, and MKK4. Breast cancer metastasis suppressor 1 (BRMS1) was identified as a suppressor of breast cancer metastasis in the late 1990s. In vitro and in vivo studies have confirmed that BRMS1 is a potent metastasis suppressor not limited to breast cancer. However, conflicting clinical observations regarding its role as a metastasis suppressor and its validity as a diagnostic biomarker warrant more in-depth clinical study. In this review, the authors provide an overview of its biology, function, action mechanism and pathological significance.

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