Upregulation of endothelial cell notch ligand jagged 1 promotes tumorigenesis and metastasis in breast cancer (58.2)

Abstract

Angiogenesis and the establishment of a vascular network by tumor‐associated endothelial cells (ECs) are well‐described in cancer. Although ECs play an essential role in tumorigenesis by constructing vasculature, other mechanisms through which ECs support tumor survival and metastasis is largely unknown. Since Notch signaling is critical for breast carcinogenesis, we investigated the potential role of ECs in mediating Notch activation. We propose that by upregulating their expression of Notch ligand Jagged 1(Jag 1), ECs induce aberrant paracrine Notch signaling in breast cancer cells, thereby providing an instructive signal for tumor growth and progression. To determine the role of EC Jag 1 expression on breast carcinogenesis, we established 3D co‐cultures of human breast cancer cells (MDA‐MB‐231) with either wild‐type or Jag 1 knockdown (KD) human umbilical vein ECs (HUVECs). We found that Jag1 loss in ECs induced decreased tumor growth, mammo‐angioshpere formation, and CD40 and CD133 expression in MDA‐231 cells. Co‐injection of Jag1 KD co‐cultures into immunocompromised mice also resulted in decreased tumor weight and volume compared to wild type co‐injections. Conditional Jag1 deletion in ECs of PyMT‐MMTV transgenic mice also led to decreased primary tumor growth and lung metastasis. These results suggest that EC Jag1 upregulation supports Notch‐dependent breast cancer cell growth and metastasisGrant Funding Source: Supported by the Howard Hughes Medical Institute