The invasive phenotype in HMT-3522 cells requires increased EGF receptor signaling through both PI 3-kinase and ERK 1,2 pathways.
We studied the invasion of HMT-3522 breast epithelial cells in response to epidermal growth factor (EGF), and the associated signaling pathways. HMT-3522 T4-2 cells were shown to invade Matrigel-coated Transwell membranes in response to EGF while HMT-3522 S-1 cells failed to invade when treated with EGF. Studies utilizing specific molecular inhibitors showed the importance of beta1 integrin, phosphatidylinositol 3 kinase (PI 3-kinase), p38, extracellular regulated kinase 1, 2 (Erk 1,2) MAP kinases, and metalloproteinases in invasion and motility. T4-2 cell invasion was shown to be time-dependent and also gene transcription-dependent as shown by inhibition with Actinomycin D. T4-2 cells exhibited an increased activation of MAP kinases Erk 1,2 (2-fold), EGF receptor (3-fold), and PI 3-kinase (3- to 4-fold) when compared to the S-1 cells. In response to EGF, T4-2 cells showed a 5-fold greater secretion of matrix metalloproteinase-9 (MMP-9) as compared to S-1 cells, and this increase was largely dependent on the activity of PI 3-kinase. These findings indicate that expression of the invasive phenotype in these breast epithelial cells requires increased EGF receptor signaling, involving both PI 3-kinase and Erk 1,2 activities, which leads to multiple downstream effects, including enhanced secretion of MMP-9 and transcription of invasion-related genes.
Price
Daniel J
DJ
Division of Experimental Medicine, Beth Israel-Deaconess Medical Center, Harvard Institutes of Medicine, Boston, MA 02115, USA.
Avraham
Shalom
S
Feuerstein
Joseph
J
Fu
Yigong
Y
Avraham
Hava Karsenty
HK
D001940:Breast / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D066246:ErbB Receptors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D039641:Integrin beta Chains / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases
D039641:Integrin beta Chains; D011500:Protein Synthesis Inhibitors; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases