Clinical profile and role of VEGF-c polymorphism in prognosis and management of breast cancer

2017 ◽  
Vol 2 (1) ◽  
pp. 11
Author(s):  
Amulya Singh ◽  
Gulab Dhar Yadav ◽  
Anand Narayan Singh ◽  
Shashwat Tiwari ◽  
Vimal Choubey
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Uttar Pradesh ◽  
Vascular Endothelial ◽  
Tumor Characteristics ◽  
Breast Cancers ◽  
Altered Expression ◽  
Dietary History ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

<span class="Bold">Purpose:</span><span> Angiogenesis is a necessary step in tumor growth and metastasis. Vascular endothelial growth factor (VEGF-c) is a major mediator of breast cancer angiogenesis. Therefore, we investigated the association of polymorphism in the VEGF-c gene with breast cancer risk and prognostic characteristics of the tumors in a case-control study. </span><span class="Bold">Experimental Design: </span><span>We examined one polymorphism in the VEGF-c gene (+936C/T) in 75 breast cancer cases and 75 control from Kanpur, Uttar Pradesh, India and adjacent areas together with geographically selected controls. </span><span class="Bold">Results:</span><span> None of the polymorphism or any haplotype was significantly associated with either breast cancers. Our study suggests that the +936C/T polymorphism is unlikely to be associated with breast cancer. We also analyzed the cases for genotypes or haplotypes that associated with tumor characteristics. The genotypes and haplotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or dietary history. </span><span class="Bold">Conclusions: </span><span>Although none of the polymorphisms studied in the VEGF-c gene was found to influence susceptibility to breast cancer significantly, some of the VEGF-c genotypes and haplotypes may influence tumor growth through an altered expression of VEGF-c and tumor angiogenesis.</span>

scholarly journals Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

2014 ◽  
Vol 204 (2) ◽  
pp. 247-263 ◽  
Author(s):  
Christine Jean ◽  
Xiao Lei Chen ◽  
Ju-Ock Nam ◽  
Isabelle Tancioni ◽  
Sean Uryu ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Cell ◽  
Stromal Cells ◽  
Barrier Function ◽  
Tumor Metastasis ◽  
Vascular Endothelial ◽  
Vascular Endothelial Cadherin ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

Pharmacological focal adhesion kinase (FAK) inhibition prevents tumor growth and metastasis, via actions on both tumor and stromal cells. In this paper, we show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is a target of FAK in tumor-associated endothelial cells (ECs). Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC-Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC-Y658 phosphorylation. Both FAK inhibition and VEC-Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. As pharmacological c-Src or FAK inhibition prevents VEGF-stimulated c-Src and FAK translocation to EC adherens junctions, but FAK inhibition does not alter c-Src activation, our experiments identify EC FAK as a key intermediate between c-Src and the regulation of EC barrier function controlling tumor metastasis.

scholarly journals Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Muriel Lainé ◽  
Sean W. Fanning ◽  
Ya-Fang Chang ◽  
Bradley Green ◽  
Marianne E. Greene ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Growth ◽  
Ligand Binding ◽  
Endocrine Therapy ◽  
Breast Cancers ◽  
Primary Tumor Growth ◽  
Wild Type ◽  
Tumor Growth And Metastasis ◽  
Anti Tumor Activity

Abstract Background Endocrine therapy remains the mainstay of treatment for estrogen receptor-positive (ER+) breast cancer. Constitutively active mutations in the ligand binding domain of ERα render tumors resistant to endocrine agents. Breast cancers with the two most common ERα mutations, Y537S and D538G, have low sensitivity to fulvestrant inhibition, a typical second-line endocrine therapy. Lasofoxifene is a selective estrogen receptor modulator with benefits on bone health and breast cancer prevention potential. This study investigated the anti-tumor activity of lasofoxifene in breast cancer xenografts expressing Y537S and D538G ERα mutants. The combination of lasofoxifene with palbociclib, a CDK4/6 inhibitor, was also evaluated. Methods Luciferase-GFP tagged MCF7 cells bearing wild-type, Y537S, or D538G ERα were injected into the mammary ducts of NSG mice (MIND model), which were subsequently treated with lasofoxifene or fulvestrant as single agents or in combination with palbociclib. Tumor growth and metastasis were monitored with in vivo and ex vivo luminescence imaging, terminal tumor weight measurements, and histological analysis. Results As a monotherapy, lasofoxifene was more effective than fulvestrant at inhibiting primary tumor growth and reducing metastases. Adding palbociclib improved the effectiveness of both lasofoxifene and fulvestrant for tumor suppression and metastasis prevention at four distal sites (lung, liver, bone, and brain), with the combination of lasofoxifene/palbociclib being generally more potent than that of fulvestrant/palbociclib. X-ray crystallography of the ERα ligand binding domain (LBD) shows that lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells. Conclusions We report for the first time the anti-tumor activity of lasofoxifene in mouse models of endocrine therapy-resistant breast cancer. The results demonstrate the potential of using lasofoxifene as an effective therapy for women with advanced or metastatic ER+ breast cancers expressing the most common constitutively active ERα mutations.

scholarly journals Microbial activation converts neutrophils into anti-tumor effectors

2020 ◽  
Author(s):  
Andrew O. Yam ◽  
Jacqueline Bailey ◽  
Francis Lin ◽  
Arnolda Jakovija ◽  
Claudio Counoupas ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Immune Cell ◽  
Vascular Endothelial ◽  
Tumor Cell Death ◽  
Two Photon Microscopy ◽  
Rational Development ◽  
Activated Neutrophils ◽  
Tumor Killing ◽  
Tumor Growth And Metastasis ◽  
Endothelial Growth Factor

ABSTRACTNeutrophils infiltrate most solid tumors and their presence is usually correlated with suppression of anti-tumor responses, metastasis and poor prognosis. Here we used microbial bioparticles administered into the tumor microenvironment to transform neutrophils into anti-tumor effectors. Microbially activated neutrophils acquired an effector phenotype associated with pathogen killing and lost vascular endothelial growth factor expression associated with tumor growth and metastasis. They became the dominant immune cell infiltrating the tumor and inhibited tumor growth. Using intravital two-photon microscopy microbially activated neutrophils could be seen forming close contacts with tumor cells resulting in tumor tissue remodeling and tumor cell death. Thus, microbial bioparticle treatment can endow neutrophils with anti-tumor properties, suggesting that neutrophil plasticity in cancer could be exploited for tumor killing. These data highlight a pathway for the rational development of neutrophil-based cancer therapy.

scholarly journals Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Xuejiao Song ◽  
Tiantao Gao ◽  
Ningyu Wang ◽  
Qiang Feng ◽  
Xinyu You ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Selective Inhibition ◽  
Breast Cancers ◽  
H3k27 Methylation ◽  
Molecule Inhibitor ◽  
Orally Bioavailable ◽  
Tumor Growth And Metastasis ◽  
Induced Apoptosis

Abstract Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer.

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