Abstract
The signals used by insulin-like growth factor I (IGF-I) to stimulate proliferation in human mammary epithelial cells have been investigated. IGF-I caused the activation of both ERKs and Akt. Activation of ERKs was slower and more transient than that of Akt. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, prevented activation of ERKs but not Akt by IGF-I. Inhibition of the EGFR with function-blocking monoclonal antibodies also specifically blocked IGF-I-induced ERK activation. These effects occurred in primary mammary epithelial cells and in two cell lines derived from normal mammary epithelium but not in mammary fibroblasts or IGF-I-responsive breast carcinoma cell lines. Although IGF-I stimulated the proliferation of both normal and carcinoma cell lines, ZD1839 blocked this only in the normal line. ZD1839 had no effect on IGF-I receptor (IGF-IR) autophosphorylation in intact cells. IGF-I-induced ERK activation was insensitive to a broad spectrum matrix-metalloproteinase inhibitor and to CRM-197, an inhibitor of the EGFR ligand heparin-bound epidermal growth factor. EGFR was detectable within IGF-IR immunoprecipitates from normal mammary epithelial cells. Treatment of cells with IGF-I led to an increase in the amount of tyrosine-phosphorylated EGFR within these complexes. ZD1839 had no effect on complex formation but completely abolished their associated EGFR tyrosine phosphorylation. These findings indicate that IGF-I utilizes a novel EGFR-dependent signaling pathway involving the formation of a complex between the IGF-IR and the EGFR to activate the ERK pathway and to stimulate proliferation in normal human mammary epithelial cells. This form of regulation may be lost during malignant progression.
Highlights
The growth, development, and normal functioning of the mammary gland are regulated by a variety of hormones, growth factors, and cytokines
Pretreatment of HB4A cells with ZD1839 (IressaTM), a highly specific inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, which blocks EGF-stimulated tyrosine phosphorylation of the EGFR and subsequent downstream signals and cellular responses [17,18,19], completely blocked the ability of EGF to promote both ERK and Akt phosphorylation (Fig. 2A). Such treatment prevented ERK phosphorylation in response to insulin-like growth factor I (IGF-I), whereas IGF-I-induced Akt phosphorylation was unaffected. These results indicate a divergence in IGF-I signaling, with an EGFR-dependent pathway leading to ERK phosphorylation and an EGFR-independent pathway leading to Akt phosphorylation
We examined the relative potency of ZD1839 in preventing ERK activation by EGF compared with IGF-I
Summary
The growth, development, and normal functioning of the mammary gland are regulated by a variety of hormones, growth factors, and cytokines. These findings indicate that IGF-I utilizes a novel EGFRdependent signaling pathway involving the formation of a complex between the IGF-IR and the EGFR to activate the ERK pathway and to stimulate proliferation in normal human mammary epithelial cells.
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