scholarly journals Two isoleucyl tRNAs that decode ‘synonymous’ codons divergently regulate breast cancer progression

2021 ◽  
Author(s):  
Lisa B. Earnest-Noble ◽  
Dennis Hsu ◽  
Hosseinali Asgharian ◽  
Mandayam Nandan ◽  
Maria C. Passarelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Genome ◽  
Cancer Progression ◽  
Human Cancer ◽  
Breast Cancer Progression ◽  
Human Cancer Cells ◽  
Functional Studies ◽  
Synonymous Codons ◽  
Growth Promoting

The human genome contains 61 codons that encode for the 20 amino acids. The synonymous codons of a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons are modulated in opposing directions during breast cancer progression. Specifically, tRNAIleUAU is upregulated, whereas tRNAIleGAU is repressed as breast cancer cells attained enhanced metastatic capacity. Functional studies revealed that tRNAIleUAU promoted and tRNAIleGAU suppressed metastatic colonization. The expression of these tRNAs mediated opposing effects on codon-dependent translation of growth promoting genes. Consistent with this, multiple mitotic gene sets in the human genome are significantly enriched in the codon cognate to the growth-promoting tRNAIleUAU and significantly depleted of the codon cognate to the growth-suppressive tRNAIleGAU. Our findings uncover a specific isoacceptor tRNA pair that act in opposition—divergently regulating genes that contribute to growth and a disease phenotype. The degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that facilitate the transition towards a growth-promoting state.

scholarly journals Sympathetic activity in breast cancer and metastasis: partners in crime

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Francisco Conceição ◽  
Daniela M. Sousa ◽  
Joana Paredes ◽  
Meriem Lamghari
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Bone Remodeling ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Sympathetic Innervation ◽  
Breast Cancer Progression ◽  
Vicious Cycle ◽  
Native Bone ◽  
Cancer Management

AbstractThe vast majority of patients with advanced breast cancer present skeletal complications that severely compromise their quality of life. Breast cancer cells are characterized by a strong tropism to the bone niche. After engraftment and colonization of bone, breast cancer cells interact with native bone cells to hinder the normal bone remodeling process and establish an osteolytic “metastatic vicious cycle”. The sympathetic nervous system has emerged in recent years as an important modulator of breast cancer progression and metastasis, potentiating and accelerating the onset of the vicious cycle and leading to extensive bone degradation. Furthermore, sympathetic neurotransmitters and their cognate receptors have been shown to promote several hallmarks of breast cancer, such as proliferation, angiogenesis, immune escape, and invasion of the extracellular matrix. In this review, we assembled the current knowledge concerning the complex interactions that take place in the tumor microenvironment, with a special emphasis on sympathetic modulation of breast cancer cells and stromal cells. Notably, the differential action of epinephrine and norepinephrine, through either α- or β-adrenergic receptors, on breast cancer progression prompts careful consideration when designing new therapeutic options. In addition, the contribution of sympathetic innervation to the formation of bone metastatic foci is highlighted. In particular, we address the remarkable ability of adrenergic signaling to condition the native bone remodeling process and modulate the bone vasculature, driving breast cancer cell engraftment in the bone niche. Finally, clinical perspectives and developments on the use of β-adrenergic receptor inhibitors for breast cancer management and treatment are discussed.

The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression

Endocrinology ◽  
2021 ◽  
Author(s):  
Amy E Baek ◽  
Natalia Krawczynska ◽  
Anasuya Das Gupta ◽  
Svyatoslav Victorovich Dvoretskiy ◽  
Sixian You ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Myeloid Cells ◽  
Breast Cancer Progression ◽  
Label Free ◽  
Tumor Growth And Metastasis ◽  
Promote Breast Cancer

Abstract Cholesterol has been implicated in the clinical progression of breast cancer, a disease that continues to be the most commonly diagnosed cancer in women. Previous work has identified the cholesterol metabolite, 27-hydroxycholesterol (27HC), as a major mediator of the effects of cholesterol on breast tumor growth and progression. 27HC can act as an estrogen receptor (ER) modulator to promote the growth of ERα+ tumors, and a liver x receptor (LXR) ligand in myeloid immune cells to establish an immune-suppressive program. In fact, the metastatic properties of 27HC require the presence of myeloid cells, with neutrophils (PMNs) being essential for the increase in lung metastasis in murine models. In an effort to further elucidate the mechanisms by which 27HC alters breast cancer progression, we made the striking finding that 27HC promoted the secretion of extracellular vesicles (EVs), a diverse assortment of membrane bound particles that include exosomes. The resulting EVs had a size distribution that was skewed slightly larger, compared to EVs generated by treating cells with vehicle. The increase in EV secretion and size was consistent across three different subtypes: primary murine PMNs, RAW264.7 monocytic cells and 4T1 murine mammary cancer cells. Label-free analysis of 27HC-EVs indicated that they had a different metabolite composition to those from vehicle-treated cells. Importantly, 27HC-EVs from primary PMNs promoted tumor growth and metastasis in two different syngeneic models, demonstrating the potential role of 27HC induced EVs in the progression of breast cancer. EVs from PMNs were taken up by cancer cells, macrophages and PMNs, but not T cells. Since EVs did not alter proliferation of cancer cells, it is likely that their pro-tumor effects are mediated through interactions with myeloid cells. Interestingly, RNA-seq analysis of tumors from 27HC-EV treated mice do not display significantly altered transcriptomes, suggesting that the effects of 27HC-EVs occur early on in tumor establishment and growth. Future work will be required to elucidate the mechanisms by which 27HC increases EV secretion, and how these EVs promote breast cancer progression. Collectively however, our data indicate that EV secretion and content can be regulated by a cholesterol metabolite, which may have detrimental effects in terms of disease progression, important findings given the prevalence of both breast cancer and hypercholesterolemia.

LncRNA NEAT1 accelerates breast cancer progression through regulating miR-410-3p/ CCND1 axis

2020 ◽  
Vol 29 (2) ◽  
pp. 277-290
Author(s):  
Xuan Liu ◽  
Weirong Yao ◽  
Haiwei Xiong ◽  
Qiang Li ◽  
Yingliang Li
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Breast Cancer Progression ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Cancer Tissues

BACKGROUND: Breast cancer is the most common malignant tumor and usually occurs in women. Studies have shown that lncRNA nuclear enriched abundant transcript 1 (NEAT1) contributes to breast cancer progression. This study intends to further investigate the molecular mechanism of NEAT1 in breast cancer. METHODS: The expression levels of NEAT1, miR-410-3p and Cyclin D1 (CCND1) were detected by quantitative real-time PCR (qRT-PCR) in breast cancer tissues and cells. Kaplan-Meier analysis and the log-rank test were performed to determine the relationship between NEAT1 and overall survival. Cell Counting Kit-8 (CCK-8) assay analyzed cell proliferation. Transwell assay was performed to examine cell migration and invasion. The protein levels of CCND1 and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, N-cadherin and Vimentin) were measured by western blot. The target relationship was predicted by bioinformatics analysis, and confirmed by luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Xenograft analysis was used to evaluate the tumor growth in vivo. RESULTS: NEAT1 and CCND1 were upregulated, while miR-410-3p was down-regulated in breast cancer tissues and cells. Higher NEAT1 expression level was associated with lower survival rate of breast cancer patients. Knockdown of miR-410-3p restored silenced NEAT1-mediated the inhibition of on proliferation, migration, invasion and EMT of breast cancer cells. In addition, NEAT1 regulated CCND1 expression by sponging miR-410-3p in breast cancer cells. NEAT1 knockdown blocked the tumor growth in vivo. CONCLUSION: NEAT1 induced breast cancer progression by regulating the miR-410-3p/CCND1 axis, indicating that NEAT1 may be a potential therapeutic target in breast cancer.

scholarly journals EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

2016 ◽  
Vol 23 (9) ◽  
pp. 747-758 ◽  
Author(s):  
Zara Zelenko ◽  
Emily Jane Gallagher ◽  
Irini Markella Antoniou ◽  
Deepali Sachdev ◽  
Anupma Nayak ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Mortality Data ◽  
Primary Tumors ◽  
Mesenchymal Transition ◽  
Insulin Resistant ◽  
Human Cancer Cells

Type 2 diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing theRag1−/−mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate theRag1−/−(Rag/WT) andRag1−/−/MKR+/+(Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher nonfasting plasma insulin levels compared with the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study, we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors,TWIST1andZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers vimentin, SLUG, TWIST1 and ZEB1, suppression of angiogenesis markers,VEGFAandVEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth-promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial–mesenchymal transition.

scholarly journals Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
William W Wheaton ◽  
Samuel E Weinberg ◽  
Robert B Hamanaka ◽  
Saul Soberanes ◽  
Lucas B Sullivan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Cellular Respiration ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Human Cancer Cells

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.

scholarly journals Arctigenin Attenuates Breast Cancer Progression through Decreasing GM-CSF/TSLP/STAT3/β-Catenin Signaling

2020 ◽  
Vol 21 (17) ◽  
pp. 6357
Author(s):  
Hui Shi ◽  
Luping Zhao ◽  
Xinlin Guo ◽  
Runping Fang ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Nuclear Translocation ◽  
Breast Cancer Progression ◽  
Gm Csf ◽  
Stat3 Phosphorylation

Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.

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