Targeting TACE-dependent EGFR ligand shedding in breast cancer

Paraic A. Kenny, Mina J. Bissell

Research output: Contribution to journalArticle

208 Citations (Scopus)

Abstract

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 that provides an oncogenic stimulus in the absence of proto-oncogene mutation. Targeting this protease, TNF-α-converting enzyme (TACE; also referred to as a disintegrin and metalloproteinase 17 [ADAM17]), with small molecular inhibitors or siRNAs reverted the malignant phenotype in a breast cancer cell line by preventing mobilization of 2 crucial growth factors, TGF-α and amphiregulin. We show that TACE-dependent ligand shedding was prevalent in a series of additional breast cancer cell lines and, in all cases examined, was amenable to inhibition. Using existing patient outcome data, we demonstrated a strong correlation between TACE and TGFA expression in human breast cancers that was predictive of poor prognosis. Tumors resulting from inappropriate activation of the EGFR were common in multiple tissues and were, for the most part, refractory to current targeted therapies. The data presented here delineate the molecular mechanism by which constitutive EGFR activity may be achieved in tumor progression without mutation of the EGFR itself or downstream pathway components and suggest that this important oncogenic pathway might usefully be targeted upstream of the receptor.

Original languageEnglish (US)
Pages (from-to)337-345
Number of pages9
JournalJournal of Clinical Investigation
Volume117
Issue number2
DOIs
StatePublished - Feb 1 2007
Externally publishedYes

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Breast Neoplasms
Ligands
Peptide Hydrolases
Disintegrins
Cell Line
Neoplasms
Mutation
Proto-Oncogenes
Metalloproteases
Intercellular Signaling Peptides and Proteins
Phenotype
Therapeutics
ADAM17 Protein
Amphiregulin

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Targeting TACE-dependent EGFR ligand shedding in breast cancer. / Kenny, Paraic A.; Bissell, Mina J.

In: Journal of Clinical Investigation, Vol. 117, No. 2, 01.02.2007, p. 337-345.

Research output: Contribution to journalArticle

Kenny, Paraic A. ; Bissell, Mina J. / Targeting TACE-dependent EGFR ligand shedding in breast cancer. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 2. pp. 337-345.
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