Abstract
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.
Highlights
Triple-negative breast cancer (TNBC) refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and Her2/neu [ 1]
At the conclusion of the experiment, the tumor volume was significantly reduced by 90.4% (p < 0.01) in the sunitinib-treated group in contrast to the control group (Figure 1 A), which was consistent with the reduction in tumor weight in the sunitinibtreated group compared to the control group (31 ± 0.6 vs. 294 ± 28 mg; P
The present study shows a new finding that sunitinib significantly increases the expression of Notch-1 in culture MDA-MB-468 cells as well as MDA-MB-231 cells even under the normoxia condition, which is consistent with increased cancer stem cells (CSCs) by sunitinib in the basal-like TNBC (MDA-MB-468) or the claudin-low TNBC xenografts
Summary
Triple-negative breast cancer (TNBC) refers to any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) and Her2/neu [ 1]. TNBCs comprise the basal and claudin-low molecular subtypes. The majority of TNBCs (approximately 80%) are basal-like breast cancers [ 4]. We previously reported that sunitinib targeted the paracrine and autocrine effects of VEGF on breast cancer to suppress tumor angiogenesis, proliferation and migration in a mouse ER-positive breast cancer model [ 11]. There were several reports that sunitinib inhibited tumor angiogenesis and tumor growth in xenografts of the claudin-low TNBC (MDA-MB-231) cells [ 15– 17]. In a phase II study in patients with heavily pretreated metastatic breast cancer, 15% of patients (three of 20) with TNBC achieved partial responses following treatment with single-agent sunitinib [ 18]. There is no reported study on anti-tumor effects of sunitinib in xenografts of the basal-like TNBC (MDA-MB-468) cells
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
