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Osteoblasts‐derived TGF‐β1 enhance motility and integrin upregulation through Akt, ERK, and NF‐κB‐dependent pathway in human breast cancer cells
Author(s) -
Wei YingYing,
Chen YingJu,
Hsiao YuChun,
Huang YiChia,
Lai TzuHsu,
Tang ChihHsin
Publication year - 2008
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20411
Subject(s) - phosphorylation , protein kinase b , mapk/erk pathway , ly294002 , biology , cancer research , iκb kinase , integrin , kinase , microbiology and biotechnology , pi3k/akt/mtor pathway , small interfering rna , signal transduction , transfection , cell culture , nf κb , cell , biochemistry , genetics
Bone metastases are common complications of breast cancer. Integrins are the major adhesive molecules in mammalian cells. Here we found that osteoblast conditioned medium (OBCM) increased the migration and cell surface expression of β1 or β3 integrin in human breast cancer cells (MDA‐MB‐231 cells). β1 or β3 integrin monoclonal antibodies (mAbs) or small interference RNA (siRNA) against β1 or β3 integrin inhibited the OBCM‐induced increase in the migration of breast cancer cells. Transforming growth factor‐β1 (TGF‐β1) siRNA could remarkably blocked OBCM‐induced chemomigration and β1 and β3 integrin expression in breast cancer cells. Stimulation of cells with OBCM caused an increase in Akt and extracellular signal‐regulated kinase (ERK) phosphorylation in a time‐dependent manner. In addition, treatment of MDA‐MB‐231 cells with phosphatidylinositol 3‐kinase inhibitor (LY294002), ERK inhibitor (PD98059), NF‐κB inhibitor (PDTC), or IκB protease inhibitor (TPCK) inhibited OBCM‐induced cells migration and integrins expression. Treatment of MDA‐MB‐231 cells with OBCM induced IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, IκBα degradation, p65 Ser 536 phosphorylation, and κB‐luciferase activity. The OBCM‐mediated increases in IKK α/β phosphorylation, p65 Ser 536 phosphorylation, and κB‐luciferase activity were inhibited by LY294002 and PD98059. In addition, TGF‐β1 siRNA also reduced the OBCM‐induced ERK, Akt, IKKα/β, IκBα, and p65 phosphorylation. Taken together, these results suggest that the osteoblast‐derived TGF‐β1 acts through Akt and ERK, which in turn activates IKKα/β and NF‐κB, resulting in the activations of β1 and β3 integrins and contributing the migration of breast cancer cell. © 2007 Wiley‐Liss, Inc.