Jab1 is a target of EGFR signaling in ERα-negative breast cancer
Date
2008-06-06
Authors
Wang, Jiaxu
Barnes, Rebecca O
West, Nathan R
Olson, Melanie
Chu, Jenny E
Watson, Peter H
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Introduction c-Jun activation domain-binding protein-1 (Jab1) is
a multifunctional signaling protein that previously has been
shown to be a master regulator of a poor prognostic gene
signature in invasive breast cancer and to mediate the action of
S100A7. Since epidermal growth factor receptor (EGFR), like
S100A7, is often expressed in estrogen receptor-alphanegative
(ERα-) breast cancer, we set out to investigate the role
of Jab1 in mediating EGFR signaling, another facet of the ERα-
phenotype.
Methods MDA-MB-231 and MDA-MB-468 ERα-/EGFR+ cell
lines were assessed for localization of Jab1 and levels of
downstream genes by immunofluorescence and nuclear protein
extract assay following treatment with epidermal growth factor
(EGF) and extracellular signal-regulated kinase (ERK) pathway
inhibitor. A cohort of 424 human breast tumors was also
assessed by immunohistochemistry.
Results EGF treatment of cell lines resulted in increased Jab1
nuclear expression. This effect was inhibited by the ERK
pathway inhibitor, PD98059. EGF treatment was also
associated with colocalization of pERK (phosphorylated ERK)
and Jab1 as well as regulation of the Jab1 downstream target
gene, p27. When Jab1 activity was knocked down, p27 levels
were restored to pre-EGF treatment level. Analysis of EGFR and
Jab1 expression in a cohort of invasive breast tumors by tissue
microarray and immunohistochemistry confirmed a relationship
between EGFR and increased nuclear Jab1 within the ERα-
subset (n = 154, P = 0.019). The same association was also
confirmed for S100A7 and Jab1 (P = 0.036), and high Jab1
nuclear expression was most frequent in tumors that were
positive for both EGFR and S100A7 (P = 0.004).
Conclusion Jab1 is a target of EGFR signaling in ERα- cell lines
and breast tumors and therefore may be a common central
factor and potential therapeutic target for important cell
signaling pathways in ERα- breast cancer.
Description
BioMed Central
Keywords
Citation
Wang et al.: Jab1 is a target of EGFR signaling in ERα-negative breast cancer. Breast Cancer Research 2008, 10:R51.