Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients

Makhoul, Issam; Тодорова, Валентина; Siegel, Eric R.; Erickson, Stephen W.; Dhakal, Ishwori; Raj, Vinay; Lee, Jeannette; Orloff, Mohammed S.; Griffin, Robert J.; Henry‐Tillman, Ronda; Klimberg, Suzanne; Hutchins, Laura F.; Kadlubar, Susan

doi:10.1371/journal.pone.0168550

Cited by 22 publications

(22 citation statements)

References 14 publications

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“…There have been multiple reports of increased levels of MMPs in breast cancer, and high expression of MMP-7 and MMP-9 has been reported to be associated with an unfavorable prognosis for patients with breast cancer (28)(29)(30). A meta-analysis also demonstrated that polymorphisms in the promoter regions of MMP-7 and MMP-9 may be associated with metastasis in breast cancer (31).…”

Section: Bcsc-1 Immunostaining [N (%)] ------------------------------mentioning

confidence: 99%

BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling

Chen

Guo

et al. 2018

Int J Oncol

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Breast cancer suppressor candidate-1 (BCSC-1; also termed von Willebrand factor A domain containing 5A and LOH11CR2A) is a newly identified candidate tumor suppressor gene that has been implicated in several types of cancer in previous studies. However, there have been few reports about the association between BCSC-1 and human breast cancer in recent years. In the present study, the expression of BCSC-1 in breast cancer was determined by immunohistochemistry (IHC) staining of tissue microarrays and clinical tissue specimens. Subsequently, BCSC-1 gene expression was evaluated in different breast cancer cell lines by quantitative polymerase chain reaction and the MDA-MB-231 cell line was selected for further use in subsequent experiments, due to its low BCSC-1 expression. An MDA-MB-231 cell line with stable overexpression of BCSC-1 was established through transfection with plasmid containing the BCSC-1 gene, and then screening for G418 resistance. Wound-healing, migration and invasion assays were conducted to detect the effect of BCSC-1 on MDA-MB-231 cells. Furthermore, changes in matrix metalloproteinases (MMPs), osteopontin (OPN) and the nuclear factor-κB (NF-κB) pathway were detected in the current study. Additionally, stable silencing of BCSC-1 expression in MCF-7 cells was performed using a lentivirus. The results of IHC indicated that BCSC-1 is expressed at low levels in breast cancer tissues compared with in normal breast tissue. Results of the wound healing, migration and invasion assays demonstrated that BCSC-1 overexpression reduced the metastasis ability of MDA-MB-231 cells in vitro. Further research confirmed that the BCSC-1 overexpression reduced the expression levels of MMP7, MMP9 and OPN, and the phosphorylation of NF-κB p65. Furthermore, inhibition of BCSC-1 via lentivirus-mediated RNA interference revealed that the downregulation of BCSC-1 increased the invasive ability of MCF-7 cells. In summary, the results demonstrated that BCSC-1 is expressed at low levels in breast cancer tissues, and that it can suppress human breast cancer cell migration and invasion, potentially altering the expression of MMP7, MMP9, OPN, and the activity of the NF-κB pathway. Therefore, BCSC-1 may be useful as a biomarker for the treatment of breast cancer in the future.

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Section: Bcsc-1 Immunostaining [N (%)] ------------------------------mentioning

confidence: 99%

BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling

Chen

Guo

et al. 2018

Int J Oncol

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“…Previous studies indicated that TEK might be promising prognosis markers in cancers such as clear cell renal carcinoma (Nakashima et al 2019). TEK was reported to be associated with the complete response to bevacizumab in breast cancer patients (Makhoul et al 2017). TEK also could modulate the interaction of glioma and brain tumor stem cells, and promote an invasive phenotype (Liu et al 2010).…”

Section: Discussionmentioning

confidence: 99%

TEK Suppresses Lung Adenocarcinoma Cell Phenotypes by Interacting with miR-19a-3p

Peng

Yang

Sun

et al. 2020

Preprint

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Abstract Background: We identified TEK as a key gene that that participates in lung adenocarcinoma cell migration and adhesion, and miR-19a-3p a potential upstream regulator of TEK. Both TEK and miR-19a-3p have been reported during lung cancer development. However, how TEK/miR-19a-3p interactome regulates lung adenocarcinoma remains unraveled. We herein aim to report a novel TEK/miR-19a-3p interactome in lung adenocarcinoma.Methods: The mRNA and protein expression of TEK in tissues and cell lines were determined using qPCR and Western blot, respectively. CCK-8 assay, EDU assay, flow-cytometry cell apoptosis assay, scratch assay, and cell-to-extracellular matrix adhesion assay were performed to detect the proliferation, apoptosis, migration, and adhesion of A549 and H1975 cell lines. Results：Both mRNA and protein levels of TEK were down-regulated in tumor tissues and cell lines. Compared with the control, the transfection of TEK overexpression plasmids into H1975 and A549 cells led to the significant inhibition of cancerous phenotypes. On the other hand, miR-19a-3p promoted lung adenocarcinoma cancerous cell phenotypes by downregulating TEK.Conclusions: TEK can be a potential LUAD tumor suppressor by interacting with miR-19a-3p. This novel interactome can be used as a novel therapy target for LUAD.

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“…Another example was reported in metastatic CRC where VEGFA rs833061 and VEGFR1 rs9513070 respectively associated with the objective response rate and the OS in subjects treated with cytotoxic chemotherapy plus bevacizumab (Sohn et al, 2014 ). Analysis of genetic variants of other angiogenic-related genes in breast cancer using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone showed a correlation between specific SNPs in term of pathologic complete response but not in OS (Makhoul et al, 2017 ).…”

Section: Mechanisms Of Resistance To Anti-angiogenic Regimensmentioning

confidence: 99%

Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies

Comunanza

Bussolino

2017

Front. Cell Dev. Biol.

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The concept that blood supply is required and necessary for cancer growth and spreading is intuitive and was firstly formalized by Judah Folkman in 1971, when he demonstrated that cancer cells release molecules able to promote the proliferation of endothelial cells and the formation of new vessels. This seminal result has initiated one of the most fascinating story of the medicine, which is offering a window of opportunity for cancer treatment based on the use of molecules inhibiting tumor angiogenesis and in particular vascular-endothelial growth factor (VEGF), which is the master gene in vasculature formation and is the commonest target of anti-angiogenic regimens. However, the clinical results are far from the remarkable successes obtained in pre-clinical models. The reasons of this discrepancy have been partially understood and well addressed in many reviews (Bergers and Hanahan, 2008; Bottsford-Miller et al., 2012; El-Kenawi and El-Remessy, 2013; Wang et al., 2015; Jayson et al., 2016). At present anti-angiogenic regimens are not used as single treatments but associated with standard chemotherapies. Based on emerging knowledge of the biology of VEGF, here we sustain the hypothesis of the efficacy of a dual approach based on targeting pro-angiogenic pathways and other druggable targets such as mutated oncogenes or the immune system.

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Germline Genetic Variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA Are Associated with Pathologic Complete Response to Bevacizumab in Breast Cancer Patients

Cited by 22 publications

References 14 publications

BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling

BCSC-1 suppresses human breast cancer metastasis by inhibiting NF-κB signaling

TEK Suppresses Lung Adenocarcinoma Cell Phenotypes by Interacting with miR-19a-3p

Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies

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