Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells

Vascular Cell

Jian-Wei Gu³  Lucio Miele²  Srinivassan Vijayakumar²  Gail C Megason¹  Shelby A Cole³  Fang Chen³  John Gibson²  Kristina L Makey³  Edmund Chinchar³ 

[1] Children’s Cancer Center, University of Mississippi Medical Center, Jackson, MS 39216, USA;Cancer Institute, University of Mississippi Medical Center, 2500 North State Street, 39216-4505 Jackson, MS, USA;Department of Physiology & Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA

关键词: Notch-1;    Breast cancer stem cell;    Apoptosis;    Migration;    Proliferation;    Angiogenesis;    Xenografts;    Basal-like triple-negative breast cancer;    Sunitinib;   

Others  :  801101
DOI  :  10.1186/2045-824X-6-12

 received in 2014-03-05, accepted in 2014-05-02,  发布年份 2014

【 摘 要 】

The majority of triple-negative breast cancers (TNBCs) are basal-like breast cancers. However there is no reported study on anti-tumor effects of sunitinib in xenografts of basal-like TNBC (MDA-MB-468) cells. In the present study, MDA-MB-231, MDA-MB-468, MCF-7 cells were cultured using RPMI 1640 media with 10% FBS. Vascular endothelia growth factor (VEGF) protein levels were detected using ELISA (R & D Systams). MDA-MB-468 cells were exposed to sunitinib for 18 hours for measuring proliferation (3H-thymidine incorporation), migration (BD Invasion Chamber), and apoptosis (ApopTag and ApoScreen Anuexin V Kit). The effect of sunitinib on Notch-1 expression was determined by Western blot in cultured MDA-MB-468 cells. 10⁶ MDA-MB-468 cells were inoculated into the left fourth mammary gland fat pad in athymic nude-foxn1 mice. When the tumor volume reached 100 mm³, sunitinib was given by gavage at 80 mg/kg/2 days for 4 weeks. Tumor angiogenesis was determined by CD31 immunohistochemistry. Breast cancer stem cells (CSCs) isolated from the tumors were determined by flow cytometry analysis using CD44⁺/CD24^- or low. ELISA indicated that VEGF was much more highly expressed in MDA-MB-468 cells than MDA-MB-231 and MCF-7 cells. Sunitinib significantly inhibited the proliferation, invasion, and apoptosis resistance in cultured basal like breast cancer cells. Sunitinib significantly increased the expression of Notch-1 protein in cultured MDA-MB-468 or MDA-MB-231 cells. The xenograft models showed that oral sunitinib significantly reduced the tumor volume of TNBCs in association with the inhibition of tumor angiogeneisis, but increased breast CSCs. These findings support the hypothesis that the possibility should be considered of sunitinib increasing breast CSCs though it inhibits TNBC tumor angiogenesis and growth/progression, and that effects of sunitinib on Notch expression and hypoxia may increase breast cancer stem cells. This work provides the groundwork for an innovative therapeutic strategy in TNBC therapy by using sunitinib plus γ-secretase inhibitor to simultaneously target angiogenesis and CSC.

【 授权许可】

   
2014 Chinchar et al.; licensee BioMed Central Ltd.

【 图 表 】

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