Induction of Ras by SAF‐1/MAZ through a feed‐forward loop promotes angiogenesis in breast cancer

Cancer Medicine

Alpana Ray¹ 

[1] Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri

关键词: Angiogenesis;    breast cancer;    Ras;    SAF‐1;    VEGF expression;   

DOI  :  10.1002/cam4.362

来源: Wiley

【 摘 要 】

Abstract

In the majority of breast cancers, overexpression and hyperactivation of Ras in the tumor microenvironment play significant role in promoting cancer cell growth, angiogenesis, and metastasis. We have previously shown that vascular endothelial growth factor (VEGF) expression in triple negative breast cancer cells is regulated, at least in part, by SAF-1 (serum amyloid A activating factor 1) transcription factor. In this study we show that transformation of normal MCF-10A breast epithelial cells by constitutively active, oncogenic Ras, induces the DNA-binding activity and transcription function of SAF-1. Furthermore, we show that inhibition of MEK/MAPK-signaling pathway prevents Ras-mediated activation of SAF-1. Interestingly, silencing of SAF-1 expression in breast cancer cells by SAF-1-specific short hairpin RNAs (shRNAs) significantly reduced H-Ras and K-Ras mRNA level. We show that SAF-1 is a direct transcriptional regulator of H-Ras and K-Ras and overexpression of SAF-1 increases H-Ras and K-Ras gene expression. Chromatin immunoprecipitation (ChIP) analyses demonstrated in vivo interaction of SAF-1 at highly purine-rich sequences present at the proximal promoter region, upstream of the transcription start site, in H-Ras and K-Ras genes. Previous studies have shown that these sequences are nuclease hypersensitive and capable of forming G4 quadruplex structure. Together, our results show the presence of a novel transactivating loop, in which, Ras and SAF-1 are interconnected. These findings will help defining molecular mechanisms of abnormal overexpression of Ras in breast tumors, which seldom show genetic Ras mutations.

【 授权许可】

CC BY   
© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.