| Title |
Genetic depletion and pharmacological targeting of αv integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models
|
|---|---|
| Published in |
Breast Cancer Research, February 2015
|
| DOI | 10.1186/s13058-015-0537-8 |
| Pubmed ID | |
| Authors |
Yihao Li, Yvette Drabsch, Philippe Pujuguet, Jiang Ren, Theo van Laar, Long Zhang, Hans van Dam, Philippe Clément-Lacroix, Peter ten Dijke |
| Abstract |
Increased expression of αv integrins is frequently associated with tumor cell adhesion, migration, invasion and metastasis, and correlates with poor prognosis in breast cancer. However, the mechanism by which αv integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of αv integrins in breast cancer also have yet to be investigated. We knocked down αv integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the αv antagonist GLPG0187. The effects of αv integrin depletion on mesenchymal markers, transforming growth factor-β (TGF-β)/Smad signaling and TGF-β-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of αv integrin on breast cancer cell migration was investigated by transwell assay in vitro, and its effect on breast cancer progression was assessed by both zebrafish and mouse xenografts in vivo. In the mouse model, GLPG0187 was administered separately, or in combination with the standard-of-care anti-resorptive agent zoledronate and the chemotherapeutic drug paclitaxel, to study the effects of combinational treatments on breast cancer metastasis. Genetic interference and pharmacological targeting of αv integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of αv integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-β/Smad response. TGF-β induced αv integrin mRNA expression and αv integrin was required for TGF-β-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-β signaling. In the mouse xenografts GLPG0187 inhibited the progression of bone metastasis. Maximum efficacy of inhibition of bone metastasis was achieved when GLPG0187 was combined with the standard-of-care metastatic breast cancer treatments. These findings show that αv integrin is required for efficient TGF-β/Smad signaling and TGF-β-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting αv integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress αv integrin. |
Mendeley readers
The data shown below were compiled from readership statistics for 75 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 1% |
| Netherlands | 1 | 1% |
| Unknown | 73 | 97% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 13 | 17% |
| Researcher | 12 | 16% |
| Student > Master | 12 | 16% |
| Student > Doctoral Student | 7 | 9% |
| Student > Bachelor | 6 | 8% |
| Other | 11 | 15% |
| Unknown | 14 | 19% |
| Readers by discipline | Count | As % |
|---|---|---|
| Agricultural and Biological Sciences | 19 | 25% |
| Biochemistry, Genetics and Molecular Biology | 17 | 23% |
| Medicine and Dentistry | 11 | 15% |
| Pharmacology, Toxicology and Pharmaceutical Science | 3 | 4% |
| Immunology and Microbiology | 2 | 3% |
| Other | 7 | 9% |
| Unknown | 16 | 21% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 25 February 2015.
All research outputs
#22,759,452
of 25,374,647 outputs
Outputs from Breast Cancer Research
#1,883
of 2,053 outputs
Outputs of similar age
#231,608
of 270,084 outputs
Outputs of similar age from Breast Cancer Research
#45
of 49 outputs
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We're also able to compare this research output to 49 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.