EGF induces epithelial-mesenchymal transition through phospho-Smad2/3-Snail signaling pathway in breast cancer cells.
Epithelial-mesenchymal transition (EMT) can contribute to tumor invasion, metastasis, and resistance to chemotherapy or hormone therapy. EMT may be induced by a variety of growth factors, such as epidermal growth factor (EGF). Most studies regarding EMT have focused on TGF-β-Smads signaling. The mechanism of EGF-induced EMT via activation of the Smad2/3 in breast cancer cells, MCF-7 and MDA-MB-231, remains unclear. The expression levels of Snail, vimentin, and fibronectin were increased by EGF treatment in a time-dependent manner, while the expression level of E-cadherin was decreased. EGF-induced nuclear co-localization of phospho-Smad2/3 and Snail and cancer cell migration were inhibited by pretreatment with an ERK1/2 inhibitor, PD98059 and a phospho-Smad2 inhibitor, SB203580. Knockdown of Smad2/3 expression suppressed EGF-induced expressions of Snail, vimentin, fibronectin, and cancer cell invasion, suggesting an acquisition of the mesenchymal and migratory phenotype in less aggressive MCF-7 cells. Moreover, MDA-MB-231 cells were shown that EGF-induced EMT, and cell invasion through ERK1/2-phospho-Smad2/3-Snail signaling pathway. We have discovered that EGF-stimulated activation of Smad2/3 upregulated several key EMT markers, inhibited E-cadherin expression, promoted EMT, enhanced migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells. Identification of this molecular mechanism may provide new molecular targets for the development of therapies for metastatic breast cancer.
Department of Pathology, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
Jinkyoung
J
Kim
Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, China.
Jienan
J
Kong
Department of Pathology, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
Hyeyoon
H
Chang
Department of Pathology, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
Hayeon
H
Kim
Department of Pathology, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
Aeree
A
Kim
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D015820:Cadherins; D005353:Fibronectins; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D000071250:Snail Family Transcription Factors; D014746:Vimentin; D004815:Epidermal Growth Factor; C093642:SB 203580
EMT; Smad2/3; breast cancer; epidermal growth factor (EGF); small interfering RNA (siRNA)