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

• Published in: Toxicology and applied pharmacology 2012-10, Vol.264 (1), p.73-83
• Main Authors: Yu, Wei, Chai, Hongyan, Li, Ying, Zhao, Haixia, Xie, Xianfei, Zheng, Hao, Wang, Chenlong, Wang, Xue, Yang, Guifang, Cai, Xiaojun, Falck, John R., Yang, Jing
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 60 APPLIED LIFE SCIENCES; AKT protein; Amidines - pharmacology; ANGIOGENESIS; ANIMAL TISSUES; Animals; Biological and medical sciences; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - genetics; Breast Neoplasms - pathology; CARCINOMAS; Cell Line, Tumor; Cell migration; CELL PROLIFERATION; Chick Embryo; Chorioallantoic Membrane; Cytochrome P-450 Enzyme System - genetics; Cytochrome P450; Cytochrome P450 Family 4; Danio rerio; DODECANOIC ACID; EMBRYOS; Endothelial cells; Extracellular signal-regulated kinase; Female; FETAL MEMBRANES; Gene expression; Gene Expression Regulation, Neoplastic; GROWTH FACTORS; Gynecology. Andrology. Obstetrics; Human Umbilical Vein Endothelial Cells; Humans; IN VITRO; IN VIVO; Intracellular levels; Lauric acid; Mammary gland; Mammary gland diseases; MAMMARY GLANDS; Medical sciences; MESSENGER-RNA; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Neovascularization, Pathologic - physiopathology; Phosphatidylinositol 3-Kinases - metabolism; PHOSPHORYLATION; Proto-Oncogene Proteins c-akt - metabolism; RNA, Messenger - metabolism; SECRETION; siRNA; TETRADECANOIC ACID; THERAPY; TIMP-2; Tissue inhibitor of metalloproteinase 2; Tissue Inhibitor of Metalloproteinase-2 - metabolism; Toxicology; Transfection; Tumors; Vascular Endothelial Growth Factor A - metabolism; VEGF-A; VEINS; Xenograft Model Antitumor Assays; Zebrafish
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.07.019

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. ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have been studied in vitro and in vivo. ► CYP4Z1 regulates expression and production of VEGF-A and TIMP-2. ► CYP4Z1-induced angiogenesis is associated with PI3K and ERK1/2 activation. ► CYP4Z1 may be an attractive target for anti-cancer therapy.