Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

Journal Article · Wed Jun 15 04:00:00 EDT 2005 · Journal of Clinical Investigation

OSTI ID:919511

Kenny, Paraic A; Bissell, Mina J

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: Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
• Sponsoring Organization: USDOE Director. Office of Science. Biological andEnvironmental Research
• DOE Contract Number: AC02-05CH11231
• OSTI ID: 919511
• Report Number(s): LBNL--60074; BnR: KP1104010
• Journal Information: Journal of Clinical Investigation, Journal Name: Journal of Clinical Investigation Journal Issue: 2 Vol. 117; ISSN JCINAO; ISSN 0021-9738
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
GROWTH FACTORS
MAMMARY GLANDS
NEOPLASMS
PATIENTS
PHENOTYPE
TUMOR CELLS