Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1

Wang, Siying; Xu, Mei; Li, Feifei; Wang, Xin; Bower, Kimberly A.; Frank, Jacqueline A.; Lu, Yao; Chen, Gang; Zhang, Zhuo; Zhang, Ke; Shi, Xianglin; Luo, Jia

doi:10.1007/s10549-011-1902-7

Cited by 67 publications

(79 citation statements)

References 31 publications

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“…In that study, ethanol promoted angiogenic activity in human umbilical vein endothelial cells by stimulating a novel Notch/Angiopoietin-1 pathway [5]. These in vitro data, and the new data in human coronary artery endothelial cells presented here, are in general agreement with the in vivo studies mentioned above demonstrating a stimulatory effect of alcohol consumption on myocardial neovessel development [26, 27] and with several other studies reporting a stimulatory effect of EtOH on angiogenesis, some looking at tumor angiogenesis [29] [30] [31] [13]. At least one group describes an inhibitory effect of EtOH on angiogenesis in the context of wound healing [14] [32].…”

Section: Discussionsupporting

confidence: 90%

Flk-1/KDR Mediates Ethanol-Stimulated Endothelial Cell Notch Signaling and Angiogenic Activity

Morrow¹,

Hatch²,

Hamm³

et al. 2014

J Vasc Res

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We previously reported that ethanol (EtOH) stimulates endothelial angiogenic activity mediated via a notch- and angiopoietin-1 (Ang-1) pathway. As crosstalk exists between notch and vascular endothelial growth factor (VEGF) signaling, we examined whether the VEGF receptor (VEGFR) Flk-1 (fetal liver kinase 1) mediates EtOH-stimulated notch signaling and angiogenic activity. Methods and Results: Treatment of human coronary artery endothelial cells (HCAECs) with EtOH (1-50 mM, 24 h) dose-dependently increased Flk-1 expression with a maximum increase observed at 25 mM EtOH. Ethanol treatment activated both Flk-1 and Flt-1 (FMS-like tyrosine kinase 1) as indicated by their phosphorylation, and subsequent stimulation of Akt. EtOH activation of Flk-1 was inhibited by the VEGFR inhibitor SU5416. Gene silencing of Flk-1 using small interfering RNA inhibited the EtOH-induced increase in notch receptors 1 and 4 and notch target gene (hairy enhancer of split-related transcription factor 1) mRNA. Knockdown of Flk-1 inhibited EtOH-induced Ang-1/Tie-2 mRNA expression and blocked EtOH-induced HCAEC network formation on Matrigel, a response that was restored by notch ligand, notch ligand delta-like ligand 4, treatment. In vivo, moderate alcohol feeding increased vascular remodeling in mouse ischemic hindlimbs. Conclusions: These data demonstrate that EtOH activates Flk-1 and Flt-1 receptors in HCAECs and promotes angiogenic activity via an Flk-1/notch pathway. These effects of EtOH may be relevant to the influence of moderate alcohol consumption on cardiovascular health.

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Section: Discussionsupporting

confidence: 90%

Flk-1/KDR Mediates Ethanol-Stimulated Endothelial Cell Notch Signaling and Angiogenic Activity

Morrow¹,

Hatch²,

Hamm³

et al. 2014

J Vasc Res

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“…Alcohol consumption is consistently associated with the risk of breast cancer (Deandrea et al ., 2008; MacMahon, 2006; Suzuki et al ., 2008). Alcohol feeding prompted mammary tumor formation (Wang et al ., 2012; Wong et al ., 2012). Our studies have demonstrated that alcohol increases Brf1 expression and Pol III gene transcription to facilitate cell transformation and tumor formation (Zhang et al ., 2013; Zhong et al ., 2011, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…Alcohol increases Brf1 expression to upregulate Pol III gene transcription in vivo and in vitro (Zhang et al ., 2013; Zhong et al ., 2011). Studies have indicated that alcohol administration induces breast tumor formation of alcohol‐fed mice (Wang et al ., 2012; Wong et al ., 2012). This finding suggests that alcohol‐caused deregulation of Pol III genes is associated with mammary tumor development.…”

Section: Introductionmentioning

confidence: 99%

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Zeng

Shi

et al. 2017

Molecular Oncology

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TFIIB‐related factor 1 (Brf1) modulates the transcription of RNA Pol III genes (polymerase‐dependent genes). Upregulation of Pol III genes enhances tRNA and 5S RNA production and increases the translational capacity of cells to promote cell transformation and tumor development. However, the significance of Brf1 overexpression in human breast cancer (HBC) remains to be investigated. Here, we investigate whether Brf1 expression is increased in the samples of HBC, and we explore its molecular mechanism and the significance of Brf1 expression in HBC. Two hundred and eighteen samples of HBC were collected to determine Brf1 expression by cytological and molecular biological approaches. We utilized colocalization, coimmunoprecipitation, and chromatin immunoprecipitation methods to explore the interaction of Brf1 with estrogen receptor alpha (ERα). We determined how Brf1 and ERα modulate Pol III genes. The results indicated that Brf1 is overexpressed in most cases of HBC, which is associated with an ER‐positive status. The survival period of the cases with high Brf1 expression is significantly longer than those with low levels of Brf1 after hormone treatment. ERα mediates Brf1 expression. Brf1 and ERα are colocalized in the nucleus. These results indicate an interaction between Brf1 and ERα, which synergistically regulates the transcription of Pol III genes. Inhibition of ERα by its siRNA or tamoxifen reduces cellular levels of Brf1 and Pol III gene expression and decreases the rate of colony formation of breast cancer cells. Together, these studies demonstrate that Brf1 is a good biomarker for the diagnosis and prognosis of HBC. This interaction of Brf1 with ERα and Brf1 itself are potential therapeutic targets for this disease.

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“…The protocol was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Detailed descriptions of our preadipocyte, HUVEC, IMR90, and MEF culture methods are in Data S1 (Supporting information) and publications (Tchkonia et al ., 2007; Wang et al ., 2012). …”

Section: Methodsmentioning

confidence: 99%

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

et al. 2016

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SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1

Cited by 67 publications

References 31 publications

Flk-1/KDR Mediates Ethanol-Stimulated Endothelial Cell Notch Signaling and Angiogenic Activity

Flk-1/KDR Mediates Ethanol-Stimulated Endothelial Cell Notch Signaling and Angiogenic Activity

Role of Brf1 interaction with ERα, and significance of its overexpression, in human breast cancer

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

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