title: Pigment epithelium-derived factor (PEDF) inhibits breast cancer metastasis by down-regulating fibronectin.
abstract: Pigment epithelium-derived factor (PEDF) plays an important role in the tumor growth and metastasis inhibition. It has been reported that PEDF expression is significantly reduced in breast cancer, and associated with disease progression and poor patient outcome. However, the exact mechanism of PEDF on breast cancer metastasis including liver and lung metastasis remains unclear. The present study aims to reveal the impact of PEDF on breast cancer. The orthotopic tumor mice model inoculated by MDA-MB-231 cells stably expressing PEDF or control cells was used to assess liver and lung metastasis of breast cancer. In vitro, migration and invasion experiments were used to detect the metastatic abilities of MDA-MB-231 and SKBR3 breast cancer cells with or without overexpression of PEDF. The metastatic-related molecules including EMT makers, fibronectin, and p-AKT and p-ERK were detected by qRT-PCR, Western blot, and Fluorescent immunocytochemistry. PEDF significantly inhibited breast cancer growth and metastasis in vivo and in vitro. Mechanically, PEDF inhibited breast cancer cell migration and invasion by down-regulating fibronectin and subsequent MMP2/MMP9 reduction via p-ERK and p-AKT signaling pathways. However, PEDF had no effect on EMT conversion in the breast cancer cells which was usually involved in cancer metastasis. Furthermore, the study showed that laminin receptor mediated the down-regulation of fibronectin by PEDF. These results reported for the first time that PEDF inhibited breast cancer metastasis by down-regulating fibronectin via laminin receptor/AKT/ERK pathway. Our findings demonstrated PEDF as a dual effector in limiting breast cancer growth and metastasis and highlighted a new avenue to block breast cancer progression.
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan Road II, Guangzhou, 510080, Guangdong, China, gaolaosao@126.com.
authors.forename: Honghai
authors.initials: H
authors.lastname: Hong
authors.forename: Ti
authors.initials: T
authors.lastname: Zhou
authors.forename: Shuhuan
authors.initials: S
authors.lastname: Fang
authors.forename: Minghan
authors.initials: M
authors.lastname: Jia
authors.forename: Zumin
authors.initials: Z
authors.lastname: Xu
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Dai
authors.forename: Cen
authors.initials: C
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qi
authors.forename: Adham Sameer A
authors.initials: AS
authors.lastname: Bardeesi
authors.forename: Zhonghan
authors.initials: Z
authors.lastname: Yang
authors.forename: Weibin
authors.initials: W
authors.lastname: Cai
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement; D015536:Down-Regulation; D005136:Eye Proteins / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009414:Nerve Growth Factors / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015843:Serpins / Q000378:metabolism*; D014162:Transfection; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D005353:Fibronectins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor