Abstract
4824
The ability to proliferate independently of signals from other cell types is a fundamental characteristic of the tumor cell. Acquisition of this phenotype is likely necessary in all cancers, but the preferred mechanism by which it is achieved is somewhat tissue specific. While common in other epithelial tumors, mutations in components downstream of the EGFR such as Ras and Raf are rare in breast tumors. Here, we analyze a model of human breast cancer progression in which this transition has occurred without mutation of these proto-oncogenes and delineate the mechanism by which growth factor signaling autonomy has been established. In this model, proliferation of the malignant cells, “T4-2”, is driven by an autocrine loop not present in non-malignant, “S1”, cells. This loop is upregulated at the earliest stage of progression toward malignancy in this model (S2) and consists of two growth factors, Amphiregulin and TGFα. We show that TACE/ADAM17 activity is required for the function of these growth factors in both normal and malignant cells and that inhibition of this protease results in downregulation EGFR pathway activity and phenocopies Iressa-induced EGFR inhibition by reverting the malignant phenotype of T4-2 cells in a 3D culture assay. Although TACE has many substrates, we demonstrate definitively that the reverting effect of TACE inhibition is a direct consequence of the inhibition of growth factor ectodomain shedding and show that TACE inhibition elicits a transcriptional profile similar to inhibition of both EGFR and MEK. We further demonstrate a strong positive correlation between TACE and TGFα expression in human breast cancers that is predictive of poor prognosis. These data implicate TACE as a therapeutically tractable enzyme, the inhibition of which effectively blocks EGFR signaling by preventing mobilization of ligands for this receptor and suggest that co-ordinate inhibition of TACE may augment the activity of EGFR inhibitors in a clinical setting.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]