Editors' ChoiceCancer

The Tribble Threat in Breast Cancer

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Science Signaling  05 Feb 2013:
Vol. 6, Issue 261, pp. ec34
DOI: 10.1126/scisignal.2004027

Notch signaling promotes cell proliferation and is associated with breast cancer and metastasis. The presence of the Notch ligand, Jagged 1 (JAG1), is a marker for poor prognosis. Through the use of large-scale kinase inhibitor screens and small interfering RNA (siRNA) screens, Izrailit et al. found that Tribbles homolog 3 (TRB3), a pseudokinase that functions as a positive regulator of the mitogen-activated protein kinase (MAPK) pathway, was a key inducer of Notch signaling in breast cancer cells. Gene set enrichment analysis indicated that increased expression of JAG1 correlated significantly with the expression of MAPK-associated genes in 51 breast cancer cell lines, and these were most strongly correlated in the triple-negative breast cancer subtype. The inhibitor screen in cultures of a Notch-induced dual-reporter human breast cancer cell line, MB231-TK-R, indicated that inhibitors targeting the kinases MEK or ERK of the MAPK pathway suppressed Notch signaling. The siRNA screen in MB231-TK-R cells showed that TRB3, which stimulates MAPK signaling, was among the top hits for modulating Notch activity. In both wild-type MB231 and triple-negative breast cancer cell lines, MEK inhibitors or TRB3 siRNA suppressed the activation of Notch and reduced the abundance of JAG1. Additionally, TRB3 knockdown decreased the abundance of the transcription factor SMAD, a target of the transforming growth factor–β (TGF-β) pathway. Additionally, TRB3 knockdown inhibited MB231 cell proliferation in vitro and in mouse xenografts. JAG1 overexpression rescued the in vitro proliferation defect. Overexpression of TRB3 in a normal mammary epithelial cell line induced the abundance of JAG1 and the phosphorylation of ERK, effects that were reversed with MEK inhibitors. Together, the findings indicated that TRB3 promotes Notch-induced tumor growth through activation of the TGF-β and MAPK pathways.

J. Izrailit, H. K. Berman, A. Datti, J. L. Wrana, M. Reedijk, High throughput kinase inhibitor screens reveal TRB3 and MAPK-ERK/TGFβ pathways as fundamental Notch regulators in breast cancer. Proc. Natl. Acad. Sci. U.S.A. 110, 1714–1719 (2013). [Abstract] [Full Text]