title: HER2 mediates epidermal growth factor-induced down-regulation of E-cadherin in human ovarian cancer cells.
abstract: Overexpression of HER2 is correlated with a poor prognosis in many types of human cancers. Due to the interaction between HER2 and other ErbB receptors, HER2 is implicated in the EGF family of ligands-regulated tumor progression. In ovarian cancer, although the relationships between HER2 amplification and patient prognosis remain controversial, the underlying molecular mechanisms of HER2-mediated tumor progression are not fully understood. Our previous studies demonstrated that EGF induces ovarian cancer cell invasion by down-regulating E-cadherin expression through the up-regulation of its transcriptional repressors, Snail and Slug. It has been shown that overexpression of HER2 down-regulates E-cadherin expression in human mammary epithelial cells. However, whether HER2 mediates EGF-induced down-regulation of E-cadherin remains unknown. In this study, we examined the potential role of HER2 in EGF-induced down-regulation of E-cadherin and increased cell invasion. We show that EGF treatment induces the interaction of EGFR with HER2 and increases the activation of HER2 in human ovarian cancer cells; we also show that these effects are diminished by knockdown of EGFR. Importantly, treatment with HER2-specific tyrosine kinase inhibitor, AG825, and HER2 siRNA diminished the up-regulation of Snail and Slug as well as the down-regulation of E-cadherin by EGF. Finally, we also show that EGF-induced cell invasion was attenuated by treatment with HER2 siRNA. This study demonstrates an important role for HER2 in mediating the effects of EGF on Snail, Slug and E-cadherin expression as well as invasiveness in human ovarian cancer cells.
authors.affiliation: Department of Obstetrics and Gynaecology, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
authors.forename: Jung-Chien
authors.initials: JC
authors.lastname: Cheng
authors.forename: Xin
authors.initials: X
authors.lastname: Qiu
authors.forename: Hsun-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Peter C K
authors.initials: PC
authors.lastname: Leung
mesh_terms: D052160:Benzothiazoles / Q000494:pharmacology; D015820:Cadherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000502:physiology*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D052160:Benzothiazoles; D015820:Cadherins; D004815:Epidermal Growth Factor; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D020032:Tyrphostins; C000604407:SNAI1 protein, human; C098214:tyrphostin AG825; C508053:ERBB2 protein, human