Angiogenesis as a therapeutic target in breast cancer

Koutras, Angelos; Starakis, Ioannis; Lymperatou, Dionysia; Kalofonos, Haralabos P.

doi:10.2174/138955712802761988

Cited by 9 publications

(2 citation statements)

References 62 publications

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“…Angiogenesis, a requisite for tumor growth, is the net result of a balance of angiogenic and antiangiogenic factors ( 1 – 3 ). Neoangiogenesis has remained a promising cancer therapeutic target for decades ( 4 – 6 ). However, the efficacy of anti-angiogenic therapies, mainly based on blocking VEGF function, has been limited in the clinical setting ( 7 – 12 ).…”

Section: Introductionmentioning

confidence: 99%

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium

et al. 2021

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Blocking tumor angiogenesis is an appealing therapeutic strategy, but to date, success has been elusive. We previously identified HEYL, a downstream target of Notch signaling, as an overexpressed gene in both breast cancer cells and as a tumor endothelial marker, suggesting that HEYL overexpression in both compartments may contribute to neoangiogenesis. Carcinomas arising in double transgenic Her2-neu/HeyL mice showed higher tumor vessel density and significantly faster growth than tumors in parental Her2/neu mice. Providing mechanistic insight, microarray-based mRNA profiling of HS578T-tet-off-HEYL human breast cancer cells revealed upregulation of several angiogenic factors including CXCL1/2/3 upon HEYL expression, which was validated by RT-qPCR and protein array analysis. Upregulation of the cytokines CXCL1/2/3 occurred through direct binding of HEYL to their promoter sequences. We found that vessel growth and migration of human vascular endothelial cells (HUVECs) was promoted by conditioned medium from HS578T-tet-off-HEYL carcinoma cells, but was blocked by neutralizing antibodies against CXCL1/2/3. Supporting these findings, suppressing HEYL expression using shRNA in MDA-MB-231 cells significantly reduced tumor growth. In addition, suppressing the action of proangiogenic cytokines induced by HEYL using a small molecule inhibitor of the CXCl1/2/3 receptor, CXCR2, in combination with the anti-VEGF monoclonal antibody, bevacizumab, significantly reduced tumor growth of MDA-MB-231 xenografts. Thus, HEYL expression in tumor epithelium has a profound effect on the vascular microenvironment in promoting neoangiogenesis. Furthermore, we show that lack of HEYL expression in endothelial cells leads to defects in neoangiogenesis, both under normal physiological conditions and in cancer. Thus, HeyL-/- mice showed impaired vessel outgrowth in the neonatal retina, while the growth of mammary tumor cells E0771 was retarded in syngeneic HeyL-/- mice compared to wild type C57/Bl6 mice. Blocking HEYL’s angiogenesis-promoting function in both tumor cells and tumor-associated endothelium may enhance efficacy of therapy targeting the tumor vasculature in breast cancer.

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Section: Introductionmentioning

confidence: 99%

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium

et al. 2021

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“…Numerous studies have shown that tumours induce sprouting angiogenesis from surrounding vasculature, which is essential for tumour growth [2,28,29]. Our previous data have shown potential roles of YB1 CTD in proliferation and differentiation VSMCs, which are major components of vessel walls and play vital roles in vascular formation, remodelling and angiogenesis [20,30,31].…”

Section: Discussionmentioning

confidence: 94%

Overexpression of YB1 C‐terminal domain inhibits proliferation, angiogenesis and tumorigenicity in a SK‐BR‐3 breast cancer xenograft mouse model

et al. 2016

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Y‐box‐binding protein 1 ( YB 1) is a multifunctional transcription factor with vital roles in proliferation, differentiation and apoptosis. In this study, we have examined the role of its C‐terminal domain ( YB 1 CTD ) in proliferation, angiogenesis and tumorigenicity in breast cancer. Breast cancer cell line SK ‐ BR ‐3 was infected with GFP ‐tagged YB 1 CTD adenovirus expression vector. An 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2H‐tetrazolium ( MTS ) proliferation assay showed that YB 1 CTD decreased SK ‐ BR ‐3 cell proliferation, and down‐regulated cyclin B1 and up‐regulated p21 levels in SK ‐ BR ‐3 cells. YB 1 CTD overexpression changed the cytoskeletal organization and slightly inhibited the migration of SK ‐ BR ‐3 cells. YB 1 CTD also inhibited secreted VEGF expression in SK ‐ BR ‐3 cells, which decreased SK ‐ BR ‐3‐induced EA .hy926 endothelial cell angiogenesis in vitro . YB 1 CTD overexpression attenuated the ability of SK ‐ BR ‐3 cells to form tumours in nude mice, and decreased in vivo VEGF levels and angiogenesis in the xenografts in SK ‐ BR ‐3 tumour‐bearing mice. Taken together, our findings demonstrate the vital role of YB 1 CTD overexpression in inhibiting proliferation, angiogenesis and tumorigenicity of breast cancer cell line SK ‐ BR ‐3.

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Cancer Stem Cells Provide New Insights into the Therapeutic Responses of Human Prostate Cancer

Frame

Maitland

2013

Stem Cells and Prostate Cancer

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Angiogenesis as a therapeutic target in breast cancer

Cited by 9 publications

References 62 publications

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium

HEYL Regulates Neoangiogenesis Through Overexpression in Both Breast Tumor Epithelium and Endothelium

Overexpression of YB1 C‐terminal domain inhibits proliferation, angiogenesis and tumorigenicity in a SK‐BR‐3 breast cancer xenograft mouse model

Cancer Stem Cells Provide New Insights into the Therapeutic Responses of Human Prostate Cancer

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