Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

Wei Yu, Hongyan Chai, Ying Li, Haixia Zhao, Xianfei Xie, Hao Zheng, Chenlong Wang, Xue Wang, Guifang Yang, Xiaojun Cai, J R Falck, Jing Yang

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation.

Original languageEnglish (US)
Pages (from-to)73-83
Number of pages11
JournalToxicology and Applied Pharmacology
Volume264
Issue number1
DOIs
StatePublished - Oct 1 2012

Keywords

  • Angiogenesis
  • Breast cancer
  • Cytochrome P450
  • TIMP-2
  • VEGF-A

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Yu, W., Chai, H., Li, Y., Zhao, H., Xie, X., Zheng, H., Wang, C., Wang, X., Yang, G., Cai, X., Falck, J. R., & Yang, J. (2012). Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer. Toxicology and Applied Pharmacology, 264(1), 73-83. https://doi.org/10.1016/j.taap.2012.07.019