Increased constitutive activity of PKB/Akt in tamoxifen resistant breast cancer MCF-7 cells.
The tamoxifen-resistant (TAM-R) MCF-7 breast cancer cell line has been used as a model to identify the signalling pathways that enable resistant cancer cells to grow independently of steroid hormones. In TAM-R cells, peptide growth factor signalling pathways appear to be important in modified cell behaviour, growth and survival. The PI3 kinase signalling components Akt1 and Akt2 are expressed at similar levels by both parental wild-type MCF-7 and TAM-R cells, but Akt1 phosphorylation is significantly increased in TAM-R cells grown under basal conditions. High levels of basal Akt, GSK3 alpha / beta and p70S6 kinase phosphorylation are all inhibited by the PI3 kinase inhibitor, LY 294002. The ligands for the EGFR/erbB1 receptor, EGF (epidermal growth factor) and TGF alpha (transforming growth factor- alpha ) demonstrate an increased ability to activate Akt in TAM-R compared with parental MCF-7 cells and it is proposed that the preferred autocrine or paracrine activation of Akt occurs via the erbB heterodimer EGFR/erbB2 in TAM-R cells. Akt phosphorylation is reduced by gefitinib ("Iressa"/ZD1839). The results suggest that the PI3 kinase pathway plays a role in proliferation of TAM-R cells and is important in the increased EGF induced membrane ruffling detected in the resistant cells. Increased Akt1 activation may contribute to the aggressive phenotype of tamoxifen resistant ER (oestrogen receptor) positive breast cancers.
Jordan
Nicola J
NJ
Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Cardiff, CF10 3XF, UK. Jordannj1@cardiff.ac.uk
Gee
Julia M W
JM
Barrow
Denise
D
Wakeling
Alan E
AE
Nicholson
Robert I
RI
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D011518:Proto-Oncogene Proteins; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; C494921:AKT2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt