A high risk of occurrence of sporadic breast cancer in individuals with the 104NN polymorphism of the COL18A1 gene

Lourenço, Gustavo Jacob; Cardoso-Filho, Cássio; Gonçales, Neiva Sellan Lopes; Shinzato, Júlia Yoriko; Zeferino, L. C.; Nascimento, Helvia; Costa, Fernando Ferreira; Gurgel, Maria Salete Costa; Lima, Carmen Sílvia Passos

doi:10.1007/s10549-006-9259-z

Cited by 30 publications

(18 citation statements)

References 16 publications

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“…This suggests that this sequence change may not be responsible for the reported high risk of occurrence of sporadic breast cancer (25) and for the influence on the age of onset of acute myeloid leukemia (26). Our finding is supported by several studies showing that the D104N polymorphism does not appear to be associated with breast cancer susceptibility or severity (38), with increased risk to develop prostate cancer (39), or with lung cancer susceptibility (40).…”

Section: Discussionmentioning

confidence: 99%

“…Integrins-The binding properties of the D104N mutant were investigated because individuals homozygous for the D104N polymorphism in the COL18A1 gene have a high risk of occurrence of sporadic breast cancer (25). In addition, this polymorphism may influence the age of onset of acute myeloid leukemia (26).…”

Section: D104n Endostatin Mutant Retains the Ability To Interact Withmentioning

confidence: 99%

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Molecular Interplay between Endostatin, Integrins, and Heparan Sulfate

Faye

Moreau

Chautard

et al. 2009

Journal of Biological Chemistry

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Endostatin is an endogenous inhibitor of angiogenesis. Although several endothelial cell surface molecules have been reported to interact with endostatin, its molecular mechanism of action is not fully elucidated. We used surface plasmon resonance assays to characterize interactions between endostatin, integrins, and heparin/heparan sulfate. ␣5␤1 and ␣v␤3 integrins form stable complexes with immobilized endostatin (K D ‫؍‬ ϳ1.8 ؋ 10؊8 M, two-state model). Two arginine residues (Arg 27 and Arg 139 ) are crucial for the binding of endostatin to integrins and to heparin/heparan sulfate, suggesting that endostatin would not bind simultaneously to integrins and to heparan sulfate. Experimental data and molecular modeling support endostatin binding to the headpiece of the ␣v␤3 integrin at the interface between the ␤-propeller domain of the ␣v subunit and the ␤A domain of the ␤3 subunit. In addition, we report that ␣5␤1 and ␣v␤3 integrins bind to heparin/heparan sulfate. The ectodomain of the ␣5␤1 integrin binds to haparin with high affinity (K D ‫؍‬ 15.5 nM). The direct binding between integrins and heparin/heparan sulfate might explain why both heparan sulfate and ␣5␤1 integrin are required for the localization of endostatin in endothelial cell lipid rafts.

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Section: Discussionmentioning

confidence: 99%

Section: D104n Endostatin Mutant Retains the Ability To Interact Withmentioning

confidence: 99%

Molecular Interplay between Endostatin, Integrins, and Heparan Sulfate

Faye

Moreau

Chautard

et al. 2009

Journal of Biological Chemistry

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“…Variations in the tumstatin gene sequence could result in compromised endogenous angiogenesis inhibition, leading to enhanced rate of tumor progression, as demonstrated for endostatin (25,26). Such genetic screening for SNPs might identify individuals who would benefit from supplemental recombinant tumstatin or tumstatin peptide to control the rate of tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

Eikesdal

Sugimoto

Birrane

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Tumstatin is an angiogenesis inhibitor that binds to ␣v␤3 integrin and suppresses tumor growth. Previous deletion mutagenesis studies identified a 25-aa fragment of tumstatin (tumstatin peptide) with in vitro antiangiogenic activity. Here, we demonstrate that systemic administration of this tumstatin peptide inhibits tumor growth and angiogenesis. Site-directed mutagenesis identified amino acids L, V, and D as essential for the antiangiogenic activity of tumstatin. The tumstatin peptide binds to ␣v␤3 integrin on proliferating endothelial cells and localizes to select tumor endothelium in vivo. Using 3D molecular modeling, we identify a putative interaction interface for tumstatin peptide on ␣v␤3 integrin. The antitumor activity of the tumstatin peptide, in combination with bevacizumab (anti-VEGF antibody), displays significant improvement in efficacy against human renal cell carcinoma xenografts when compared with the single-agent use. Collectively, our results demonstrate that tumstatin peptide binds specifically to the tumor endothelium, and its antiangiogenic action is mediated by ␣v␤3 integrin, and, in combination with an anti-VEGF antibody it exhibits enhanced tumor suppression of renal cell carcinoma.angiogenesis ͉ ␣v␤3 integrin ͉ bevacizumab ͉ tumstatin peptide

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“…For example, COL8A1 is a collagen subtype targeted by clostridium collagenase histolyticum. 40,41 Interestingly, clostridium histolyticum is associated with colorectal metastases formation. The generation of a metastases network pathway from consensus profile components thus provides a fertile ground for investigation of novel therapeutic targets in metastasis formation.…”

Section: Discussionmentioning

confidence: 99%

Introducing a Novel and Robust Technique for Determining Lymph Node Status in Colorectal Cancer

et al. 2014

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Objective: This study aims to harness the potential of public gene expression repositories, to develop gene expression profiles that could accurately determine nodal status in colorectal cancer. Background: Currently, techniques that determine lymph node positivity (before resection) have poor sensitivity and specificity. The ability to determine lymph node status, based on preoperative biopsies, would greatly assist in planning treatment in colorectal cancer. This is particularly relevant in polypdetected cancers. Methods: Public gene expression repositories were screened for experiments comparing metastatic and nonmetastatic colorectal cancer. A customized graphic user interface was developed to extract genes dysregulated across most identified studies (ie, consensus profiles). The utility of consensus profiles was tested by determining whether classifiers could be derived that determined nodal positivity or negativity. Consensus profiles-derived classifiers were tested on separate Affymetrix-and Illumina-based experiments, and collated outputs were compiled in summary receiver operator curve characteristic format, with area under the curve (AUC) reflecting accuracy. The association between classification and oncologic outcome was determined using an additional, independent data set. Final validation was conducted using the Ingenuity network-linkage environment. Results: Four consensus profiles were generated from which classifiers were derived that accurately determined node positive and negative status (pooled AUC were 0.79 ± 0.04 and 0.8 ± 0.03 for nodal positivity and negativity, respectively). Overall AUC ranged from 0.73 to 0.86, demonstrating high accuracy across consensus profile type, classification technique, and array platform used. As consensus profile enabled classification of nodal status, survival outcomes could be compared for those predicted node negative or positive. Patterns of disease-free and overall survival were identical to those observed for standard histopathologic nodal status. Genes contained within consensus profiles were strongly linked to the metastatic process and included (among others) FYN, WNT5A, COL8A1, BMP, and SMAD family members. Conclusions: Microarray expression data available in public gene expression repositories can be harnessed to generate consensus profiles. The latter are a source of classifiers that have prognostic and predictive properties.

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A high risk of occurrence of sporadic breast cancer in individuals with the 104NN polymorphism of the COL18A1 gene

Cited by 30 publications

References 16 publications

Molecular Interplay between Endostatin, Integrins, and Heparan Sulfate

Molecular Interplay between Endostatin, Integrins, and Heparan Sulfate

Identification of amino acids essential for the antiangiogenic activity of tumstatin and its use in combination antitumor activity

Introducing a Novel and Robust Technique for Determining Lymph Node Status in Colorectal Cancer

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