Smad7 acts as a negative regulator of the epidermal growth factor (EGF) signaling pathway in breast cancer cells.
Although it has been suggested that smad7 blocks downstream signaling of TGF-β, the role of smad7 in the EGF signaling pathway has not been fully elucidated. We determined the effect of smad7 on EGF-induced MMP-9 expression in SKBR3 breast cancer cells. The expression of smad7 and MMP-9 was increased by EGF or TGF-β1, respectively, and further increased by EGF and TGF-β1 co-treatment. EGF induced the phosphorylation of EGFR, smad3, ERK, and JNK, and MMP-9 expression was decreased by the EGFR inhibitor, AG1478. In addition, EGF-induced MMP-9 expression was inhibited by UO126 (a MEK1/2 inhibitor) or SIS3 (a smad3 inhibitor), but not by SP600125 (a JNK inhibitor). Interestingly, EGF-induced smad3 phosphorylation was completely blocked by smad7 over-expression, but not the phosphorylation of ERK and JNK. EGF- or TGF-β1-induced MMP-9 expression was completely decreased by adenoviral-smad7 (Ad-smad7) over-expression. We also investigated the role of smad3 on EGF-induced MMP-9 expression and showed that EGF-induced MMP-9 expression was decreased by smad3 siRNA transfection, whereas EGF-induced MMP-9 expression was further increased by smad3 over-expression, as expected. This study showed that EGF-induced smad3 phosphorylation mediates the induction of MMP-9, whereas smad7 inhibits TGF-β1 as well as the EGF signaling pathway in SKBR3 cells.
Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
Sangmin
S
Kim
Jeonghun
J
Han
Se Kyung
SK
Lee
Minyoung
M
Koo
Dong Hui
DH
Cho
Soo Youn
SY
Bae
Min-Young
MY
Choi
Jee Soo
JS
Kim
Jung-Han
JH
Kim
Jun-Ho
JH
Choe
Jung-Hyun
JH
Yang
Seok Jin
SJ
Nam
Jeong Eon
JE
Lee
D000873:Anthracenes / Q000494:pharmacology; D001943:Breast Neoplasms / Q000473:pathology*; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D051900:Smad3 Protein / Q000502:physiology; D051906:Smad7 Protein / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D000873:Anthracenes; D002070:Butadienes; D009570:Nitriles; D012333:RNA, Messenger; C497790:SMAD3 protein, human; C497806:SMAD7 protein, human; D051900:Smad3 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; C113580:U 0126; C432165:pyrazolanthrone; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9