scholarly journals A Folate- and Vitamin B12-Deficient Diet Decreases the Latency and Increases the Incidence of Mammary Tumors in MMTV-ErbB2 Transgenic Mice

2021 ◽  
Author(s):  
Zhengzheng Xiao ◽  
Guoliang Yao ◽  
Yongxuan Liu ◽  
Chunling Zhao
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Vitamin B12 ◽  
Signaling Pathways ◽  
Mammary Tumor ◽  
Receptor Tyrosine Kinase ◽  
Tumor Development ◽  
Deficient Diet ◽  
Tyrosine Kinase 2 ◽  
Folate And Vitamin B12

Abstract There has been controversy regarding folate- and vitamin B12-deficient diet (FVD)-induced hyperhomocysteinemia (HHcy) associated with breast cancer risk in most published epidemiological studies. Thus, the present study designed experiments to assess the causal association between FVD-induced HHcy and mammary tumor risk, as well as to identify the relative underlying mechanism. In this study, mammary tumor development was examined in mouse mammary tumor virus (MMTV)-erb-b2 receptor tyrosine kinase 2 (ErbB2) mice fed with a control AIN-93G diet or a FVD diet. MMTV-ErbB2 mice fed with the FVD diet displayed elevated blood levels of the amino acid homocysteine, a shorter tumor latency and an increased tumor multiplicity compared with the controls. The expression levels of key markers in the receptor tyrosine kinase and estrogen receptor (ER) signaling pathways, including phosphorylated (p)-Akt, p-Erk, p-ERα and Cyclin D1, were elevated in mammary tissues from MMTV-ErbB2 mice fed the FVD diet compared with mice fed with control diet. These data suggested that FVD-induced HHcy may promote mammary tumor development and decrease tumor latency, possibly by activating the epidermal growth factor receptor/ErbB2 and ERα signaling pathways. Therefore, examining the signaling mechanisms and identifying the relative metabolic pathways underlying mammary tumor promotion following FVD-induced HHcy may provide a novel strategy for breast cancer prevention and treatment.

scholarly journals Differential expression of neurotrophic receptor tyrosine kinase 2 in cancers of the breast.

2021 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Differential Expression ◽  
Receptor Tyrosine Kinase ◽  
Survival Data ◽  
Normal Breast ◽  
Differentially Expressed ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Tyrosine Kinase 2

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding neurotrophic receptor tyrosine kinase 2, NTRK2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. NTRK2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of NTRK2 in primary tumors of the breast was correlated with recurrence-free survival in patients with basal, luminal A, and luminal B subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. NTRK2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

scholarly journals Erb-b2 Receptor Tyrosine Kinase 2 (ERBB2) Promotes ATG12-Dependent Autophagy Contributing to Treatment Resistance of Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1038
Author(s):  
Yongqiang Chen ◽  
Ruobing Wang ◽  
Shujun Huang ◽  
Elizabeth S. Henson ◽  
Jayce Bi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Cells ◽  
Treatment Resistance ◽  
Tyrosine Kinase 2 ◽  
Positive Breast Cancer ◽  
In Cells

The epidermal growth factor receptor (EGFR) family member erb-b2 receptor tyrosine kinase 2 (ERBB2) is overexpressed in many types of cancers leading to (radio- and chemotherapy) treatment resistance, whereas the underlying mechanisms are still unclear. Autophagy is known to contribute to cancer treatment resistance. In this study, we demonstrate that ERBB2 increases the expression of different autophagy genes including ATG12 (autophagy-related 12) and promotes ATG12-dependent autophagy. We clarify that lapatinib, a dual inhibitor for EGFR and ERBB2, promoted autophagy in cells expressing only EGFR but inhibited autophagy in cells expressing only ERBB2. Furthermore, breast cancer database analysis of 35 genes in the canonical autophagy pathway shows that the upregulation of ATG12 and MAP1LC3B is associated with a low relapse-free survival probability of patients with ERBB2-positive breast tumors following treatments. Downregulation of ERBB2 or ATG12 increased cell death induced by chemotherapy drugs in ERBB2-positive breast cancer cells, whereas upregulation of ERBB2 or ATG12 decreased the cell death in ERBB2-negative breast cancer cells. Finally, ERBB2 antibody treatment led to reduced expression of ATG12 and autophagy inhibition increasing drug or starvation-induced cell death in ERBB2-positive breast cancer cells. Taken together, this study provides a novel approach for the treatment of ERBB2-positive breast cancer by targeting ATG12-dependent autophagy.

scholarly journals Heregulin Co-opts PR Transcriptional Action Via Stat3 Role As a Coregulator to Drive Cancer Growth

2015 ◽  
Vol 29 (10) ◽  
pp. 1468-1485 ◽  
Author(s):  
Cecilia J. Proietti ◽  
Franco Izzo ◽  
María Celeste Díaz Flaqué ◽  
Rosalía Cordo Russo ◽  
Leandro Venturutti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Cancer Growth ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus ◽  
Virus Promoter

Abstract Accumulated findings have demonstrated the presence of bidirectional interactions between progesterone receptor (PR) and the ErbB family of receptor tyrosine kinases signaling pathways in breast cancer. We previously revealed signal transducer and activator of transcription 3 (Stat3) as a nodal convergence point between said signaling pathways proving that Stat3 is activated by one of the ErbBs' ligands, heregulin (HRG)β1 via ErbB2 and through the co-option of PR as a signaling molecule. Here, we found that HRGβ1 induced Stat3 recruitment to the promoters of the progestin-regulated cell cycle modulators Bcl-XL and p21CIP1 and also stimulated Stat3 binding to the mouse mammary tumor virus promoter, which carries consensus progesterone response elements. Interestingly, HRGβ1-activated Stat3 displayed differential functions on PR activity depending on the promoter bound. Indeed, Stat3 was required for PR binding in bcl-X, p21CIP1, and c-myc promoters while exerting a PR coactivator function on the mouse mammary tumor virus promoter. Stat3 also proved to be necessary for HRGβ1-induced in vivo tumor growth. Our results endow Stat3 a novel function as a coregulator of HRGβ1-activated PR to promote breast cancer growth. These findings underscore the importance of understanding the complex interactions between PR and other regulatory factors, such as Stat3, that contribute to determine the context-dependent transcriptional actions of PR.

scholarly journals Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 513 ◽  
Author(s):  
Marina Leite ◽  
Miguel S. Marques ◽  
Joana Melo ◽  
Marta T. Pinto ◽  
Bruno Cavadas ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Receptor Activation ◽  
Degradation Pathway ◽  
Mrna Levels ◽  
H Pylori

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.

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