NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways

Daly, J.M.; Olayioye, Monilola A.; Wong, Agnes M-L; Neve, Richard M.; Lane, Heidi A.; Maurer, Fabienne; Hynes, Nancy E.

doi:10.1038/sj.onc.1202700

Cited by 84 publications

(89 citation statements)

References 56 publications

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“…In other cell systems, delayed activation of the p38 MAP kinase pathway also has a negative impact on cell proliferation by inducing apoptosis (Daly et al, 1999;Takekawa et al, 2002;Bulavin and Fornace, 2004;Naito et al, 2004). Treatment of BT474 and SKBr3 cells with anti-HER2 antibodies for 72 h does not induce significant apoptosis (Le et al, 2003(Le et al, , 2005a.…”

Section: Discussionmentioning

confidence: 99%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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We determined the impact of HER2 signaling on two proangiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), and on an antiangiogenic factor, thrombospondin-1 (TSP-1). Re-expression of HER2 in MCF-7 and T-47D breast cancer cells that endogenously express low levels of HER2 resulted in elevated expression of VEGF and IL-8 and decreased expression of TSP-1. Inhibition of HER2 with a humanized anti-HER2 antibody (trastuzumab, or Herceptin s ) or a retrovirus-mediated small interfering RNA against HER2 (siHER2) decreased VEGF and IL-8 expression, but increased TSP-1 expression in BT474 breast cancer cells that express high levels of HER2. These in vitro results were further evaluated by treatment of BT474 xenografts in immunosuppressed mice with trastuzumab. Trastuzumab inhibited growth of BT474 xenografts and decreased microvascular density associated with downregulation of VEGF and IL-8 and with upregulation of TSP-1 expression. Inhibiting the PI3K-AKT pathway decreased VEGF and IL-8 expression. AKT1 overexpession increased VEGF and IL-8 expression, but did not increase TSP-1 expression. A p38 kinase inhibitor, SB203580, instead blocked TSP-1 expression and a p38 activator, MKK6, increased TSP-1 expression. Trastuzumab stimulated sustained p38 activation and SB203580 attenuated the TSP-1 upregulation induced by trastuzumab. HER2 signaling therefore influences the equilibrium between pro-and antiangiogenic factors via distinct signaling pathways. Trastuzumab inhibits angiogenesis and tumor growth, at least in part, through activation of the HER2-p38-TSP-1 pathway and inhibition of the HER2-PI3K-AKT-VEGF/IL-8 pathway.

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Section: Discussionmentioning

confidence: 99%

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

et al. 2006

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“…We observed that c-Myc protein levels ( Figure 6a) and mRNA levels ( Figure 6b, panel 1) decreased following scFv-5R induction. Similarly, when SKBr3 cells were treated with an ErbB2 inhibitor (PD153035) (Arteaga et al, 1997;Daly et al, 1999), a PI3 kinase inhibitor (LY294002) or a MEK1 inhibitor (PD 98059), each of the inhibitors caused a decrease in c-Myc mRNA levels ( Figure 6b, panels 2 and 3). The e ect of PD153035 was equivalent to 72 h of ErbB2 down-regulation (Figure 6b, panel 1 vs 3).…”

Section: C-myc Is Pivotal In Erbb2-mediated Proliferationmentioning

confidence: 90%

“…We next investigated the e ects of ErbB2 downregulation on the kinases ERK1/ERK2, Akt/PKB and p70 S6K that are stimulated in response to ErbB receptor activation Karunagaran et al, 1996;Daly et al, 1999). ERK1/ ERK2 were examined using an antiserum speci®c for the dually phosphorylated, active form of the kinases.…”

Section: Effects Of Erbb2 Down-regulation On Intracellular Signallingmentioning

confidence: 99%

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

et al. 2000

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The ErbB2 receptor tyrosine kinase is overexpressed in a variety of human tumours. In order to understand the mechanism by which ErbB2 mediates tumour proliferation we have functionally inactivated the receptor using an intracellularly expressed, ER-targeted single-chain antibody (scFV-5R). Inducible expression of scFv-5R in the ErbB2-overexpressing SKBr3 breast tumour cell line leads to loss of plasma membrane localized ErbB2. Simultaneously, the activity of ErbB3, MAP kinase and PKB/Akt decreased dramatically, suggesting that active ErbB2/ErbB3 dimers are necessary for sustained activity of these kinases. Loss of functional ErbB2 caused the SKBr3 tumour cells to accumulate in the G1 phase of the cell cycle. This was a result of reduction in CDK2 activity, which was mediated by a re-distribution of p27 Kip1 from sequestering complexes to cyclin E/CDK2 complexes. The level of c-Myc and D-cyclins, proteins involved in p27 Kip1 sequestration, decreased in the absence of functional ErbB2. Ectopic expression of c-Myc led to an increase in D cyclin levels, CDK2 activity and resulted in a partial G1 rescue. We propose that c-Myc is a primary e ector of ErbB2-mediated oncogenicity and functions to prevent normal p27 Kip1 control of cyclinE/CDK2.

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“…209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway. 228 Contributions of ERBB3 and/or the ERBB2/ ERBB3 complex to these phenotypic effects of NRG has been confirmed by use of anti-ERBB2 or anti-ERBB3 antibodies 211,212,229 or of a dominant-negative ERBB3 construct. 230 The downstream participation of PI3K or pAKT was confirmed in some of these studies by use of pharmacological or dominant-negative inhibitors of PI3K 209 or by constitutively active constructs of the p110 catalytic subunit of PI3K and by pharmacological inhibition of AKT.…”

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 92%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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NDF/heregulin-induced cell cycle changes and apoptosis in breast tumour cells: role of PI3 kinase and p38 MAP kinase pathways

Cited by 84 publications

References 56 publications

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy

Effects of oncogenic ErbB2 on G1 cell cycle regulators in breast tumour cells

The ERBB3 receptor in cancer and cancer gene therapy

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