Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer
The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, we demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.
- Research Organization:
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
- Sponsoring Organization:
- USDOE Director. Office of Science. Biological andEnvironmental Research
- DOE Contract Number:
- DE-AC02-05CH11231
- OSTI ID:
- 919511
- Report Number(s):
- LBNL-60074; JCINAO; R&D Project: 443180; BnR: KP1104010; TRN: US200822%%381
- Journal Information:
- Journal of Clinical Investigation, Vol. 117, Issue 2; Related Information: Journal Publication Date: 02/2007; ISSN 0021-9738
- Country of Publication:
- United States
- Language:
- English
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