Silencing of the PP2A catalytic subunit causes HER-2/neu positive breast cancer cells to undergo apoptosis.
Protein phosphatase 2A (PP2A), in its activated form as a phosphatase, is a tumour suppressor. However, when PP2A is phosphorylated at the tyrosine residue (pY307), it loses its phosphatase activity and becomes inactivated. In our previous study, we found a higher expression of pY307-PP2A in HER-2/neu positive breast tumour samples and significantly correlated to tumour progression, and in this context, it could function as a proto-oncogene. The above and subsequent findings led us to postulate that the critical role of PP2A in maintaining the balance between cell survival and cell death may be linked to its phosphorylation status at its Y307 residue. Hence, we further investigated the effects of knocking down the PP2A catalytic subunit which contains the Y307 amino acid residue in two HER-2/neu positive breast cancer cell lines, BT474 and SKBR3. We showed that this causes the silenced HER-2/neu breast cancer cells to undergo apoptosis and furthermore, that such apoptosis is mediated by p38 MAPK-caspase 3/PARP activation. Understanding the role of PP2A in HER2/neu positive cells might thus provide insight into new targets for breast cancer therapy.
Wong
Lee Lee
LL
Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Zhang
Daohai
D
Chang
Chan Fong
CF
Koay
Evelyn S C
ES
D017209:Apoptosis / Q000235:genetics*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000235:genetics; D020868:Gene Silencing; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology; D008954:Models, Biological; D018832:Molecular Chaperones; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000172:deficiency* / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053148:Caspase 3; D048049:Extracellular Signal-Regulated MAP Kinases; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010744:Phosphoric Monoester Hydrolases; D011065:Poly(ADP-ribose) Polymerases; D054648:Protein Phosphatase 2; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C057725:HSPB1 protein, human; C000715470:MAS1 protein, human; C508053:ERBB2 protein, human; C023210:tyrosine phosphate hydrolase; C517189:PPP2CA protein, human