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Title: Heregulin-Enhanced Tyrosine Phosphorylation in Breast Cancer Cells: Role of PP2A in HER-2/neu Oncogenic Signalling
Keywords: HER-2/neu, Phosphorylation, Heregulin, PP2A, Apoptosis, p38 MAPK
Issue Date: 22-Jul-2010
Citation: WONG LEE LEE (2010-07-22). Heregulin-Enhanced Tyrosine Phosphorylation in Breast Cancer Cells: Role of PP2A in HER-2/neu Oncogenic Signalling. ScholarBank@NUS Repository.
Abstract: HER-2/neu is an established adverse prognostic factor of breast cancer. Patients with tumours overexpressing HER-2/neu have significantly shortened overall survival. Studying the mechanisms by which HER-2/neu overexpression translate into the more aggressive biological phenotype would not only provide a better understanding of the increased virulence of breast cancers overexpressing this oncogene but may also lead to rational targeted therapeutic strategies to arrest cancer growth. Activation of HER-2/neu leads to activation or suppression of multiple signalling cascades and plays a vital role in cell survival and growth. A signal transduction antibody array was used in this study to characterize the tyrosine phosphorylation profiles in heregulin (HRG)-treated BT474 breast cancer cells.A group of 80 molecules in which tyrosine phosphorylation was highly regulated by HRG-enhanced HER-2/neu signalling was identified. These phosphoproteins included many known HER-2/neu-regulated molecules (e.g., Shc, AKT, Syk and Stat1) and proteins that had not been previously linked to HER-2/neu signalling, such as Fas-associated death domain protein (FADD), apoptosis repressor with CARD domain (ARC), and protein phosphatase type 2A (PP2A). Pharmacological inhibition with the HER-2/neu inhibitor AG825, PI3K inhibitor LY294002, MEK1/2 inhibitor PD98095, and p38 MAPK inhibitor SB203580, confirmed that PP2A phosphorylation was modulated by the complicated, HER-2/neu-driven downstream signalling network, with the PI3K and MEK1/2 positively, while the p38 MAPK negatively, regulating its tyrosine phosphorylation. In breast tumour specimens and cell lines, expression of tyrosine307-phosphorylated PP2A (pY307-PP2A) was highly increased in the HER-2/neu-positive breast tumours and cell lines, and significantly correlated to tumour progression, thus enhancing its potential prognostic value. The data in this thesis provides meaningful information in the elucidation of the HER-2/neu-driven tyrosine phosphorylation network, and in the development of phosphopeptide-related targets as prognostication indicators. 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. A higher expression of pY307-PP2A in HER-2/neu- positive breast tumour samples, which was significantly correlated to tumour progression was reported here, and in this context, PP2A 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, further investigatation on 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 were carried out. The results showed that this caused the silenced HER-2/neu breast cancer cells to undergo apoptosis and furthermore, that such apoptosis was mediated by p38 MAPK-caspase 3/ PARP activation. Understanding the role of PP2A in HER-2/neu-positive cells might thus provide insight into new targets for breast cancer therapy.
Appears in Collections:Ph.D Theses (Open)

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