Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells.
Addition of the ErbB-ligand, Heregulinbeta1 (HRG), to breast tumour-derived T47D cells promotes D-cyclin expression, p21(cip1) synthesis, cyclin-dependent kinase (CDK) activation through re-distribution of p27(kip1) and DNA synthesis. In contrast EGF has no effect on T47D cell cycle progression. By comparing these two ligands and the use of specific inhibitors for phosphatidylinositol-3 kinase (PI3K), mitogen-activated protein kinase (MAPK) and p38MAPK, we have identified several molecular mechanisms required for ErbB receptor-mediated proliferation. The PI3K, MAPK and p38MAPK pathways each displayed distinct activation profiles in response to either HRG or EGF, with obvious differences in both the intensity and duration of signal output. Through inhibition of each of these pathways it is apparent that each pathway is necessary, yet insufficient alone, to stimulate proliferation. Each pathway regulates distinct subsets of essential cell cycle regulators and integration of these signal networks is required for the timely expression of these components, which culminates in cell cycle progression. Significantly, the mechanisms controlling ligand-stimulated proliferation through ErbB2 are strikingly similar to the mechanisms through which overexpressed, constitutively activated, ErbB2 orchestrates uncontrolled proliferation in cancer cells. This suggests that downstream effectors of ErbB receptors represent good therapeutic targets for breast cancer.
Neve
Richard M
RM
Department of Hematology/Oncology, UCSF San Francisco and Buck Institute, Novato, California 94945, USA. rneve@buckinstitute.org
Holbro
Thomas
T
Hynes
Nancy E
NE
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016213:Cyclins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D016213:Cyclins; D004791:Enzyme Inhibitors; D008024:Ligands; D020890:Neuregulin-1; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases