title: Akt- and MAPK-mediated activation and secretion of MMP-9 into stroma in breast cancer cells upon heregulin treatment.
abstract: Several peptides, such as epidermal growth factor (EGF), heregulin (HRG) and transforming growth factor alpha (TGFα), are ligands for EGFR family. Heregulin beta 1 (HRG-β1) binds to ErbB-3 and -4 and plays important roles in the proliferation and tumorigenesis of breast cancer cells. We investigated proteins through which HRG treatment affects matrix metalloproteinase (MMP)-9 activity. Breast cancer cell lines, including SK-Br3, MCF-7 and MDA-MB-231, were treated with HRG-β1. After 24 h, the activity and expression levels of MMP-9 were increased, but MMP-2 activity was not changed. The increasing rates of MMP-9 activity and expression were most prominent in the SK-Br3 cell line. Upon treatment of SK-Br3 cells with HRG-β1, phosphorylation of Akt was increased showing a peak at 30 min after treatment, and the level decreased after 6 h. The expression levels of Akt were not changed upon HRG-β1 treatment. Phosphorylation of extracellular signal-regulated kinase 1/2 (ERK-1/2), downstream molecules of Akt, was also increased by HRG-β1 treatment. Pretreatment of LY294002, PI3K inhibitor, or PD98059, MAPK inhibitor, partially blocked the heregulin-induced MMP-9 activity. Furthermore, MMP-9 was found to be secreted in human breast cancer tissues. The present results suggest that Akt and MAPK mediate HRG-β1 signaling to MMP-9.
authors.affiliation: Department of Pathology, College of Medicine, Korea University, Seoul 152-703, Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Cho
authors.forename: Moon Jung
authors.initials: MJ
authors.lastname: Chae
authors.forename: Bong Kyung
authors.initials: BK
authors.lastname: Shin
authors.forename: Han Kyeom
authors.initials: HK
authors.lastname: Kim
authors.forename: Aeree
authors.initials: A
authors.lastname: Kim