| 1. |
- Li, Yihao, et al.
(author)
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Genetic depletion and pharmacological targeting of alpha v integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models
- 2015
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In: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 17
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Journal article (peer-reviewed)abstract
- Introduction: Increased expression of alpha v 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 alpha v integrins can enhance breast cancer progression is still largely unclear. The effects of therapeutic targeting of alpha v integrins in breast cancer also have yet to be investigated. Methods: We knocked down alpha v integrin in MDA-MB-231 and MCF10A-M4 breast cancer cells, or treated these cells with the alpha v antagonist GLPG0187. The effects of alpha v integrin depletion on mesenchymal markers, transforming growth factor-beta (TGF-beta)/Smad signaling and TGF-beta-induced target gene expression were analyzed in MDA-MB-231 cells by RNA analysis or Western blotting. The function of alpha v 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. Results: Genetic interference and pharmacological targeting of alpha v integrin with GLPG0187 in different breast cancer cell lines inhibited invasion and metastasis in the zebrafish or mouse xenograft model. Depletion of alpha v integrin in MDA-MB-231 cells inhibited the expression of mesenchymal markers and the TGF-beta/Smad response. TGF-beta induced alpha v integrin mRNA expression and alpha v integrin was required for TGF-beta-induced breast cancer cell migration. Moreover, treatment of MDA-MB-231 cells with non-peptide RGD antagonist GLPG0187 decreased TGF-beta 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. Conclusion: These findings show that alpha v integrin is required for efficient TGF-beta/Smad signaling and TGF-beta-induced breast cancer cell migration, and for maintaining a mesenchymal phenotype of the breast cancer cells. Our results also provide evidence that targeting alpha v integrin could be an effective therapeutic approach for treatment of breast cancer tumors and/or metastases that overexpress alpha v integrin.
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| 2. |
- Windahl, Sara H, 1971, et al.
(author)
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Bone protection by estrens occurs through non-tissue-selective activation of the androgen receptor.
- 2006
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In: The Journal of clinical investigation. - 0021-9738. ; 116:9, s. 2500-9
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Journal article (peer-reviewed)abstract
- The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-alpha and estren-beta) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.
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