The involvement of ErbB family members in
breast cancer progression and
metastasis has been demonstrated by many studies. However, the downstream effectors that mediate their migratory and invasive responses have not been fully explored. In this study, we show that the non-
receptor tyrosine kinase PYK2 is a key effector of EGFR and HER2 signaling in human
breast carcinoma. We found that PYK2 is activated by both
EGF and
heregulin (
HRG) in
breast cancer cells, and positively regulates
EGF/
HRG-induced cell spreading, migration and invasion. PYK2 depletion markedly affects ERK1/2 and STAT3 phosphorylation in response to
EGF/
HRG as well as to
IL8 treatment. Importantly, PYK2 depletion also reduced
EGF/
HRG-induced MMP9 and
IL8 transcription, while
IL8 inhibition abrogated
EGF-induced MMP9 transcription and attenuated cell invasion.
IL8, which is transcriptionally regulated by STAT3 and induces PYK2 activation, prolonged
EGF-induced PYK2, STAT3 and ERK1/2 phosphorylation suggesting that
IL8 acts through an autocrine loop to reinforce
EGF-induced signals. Collectively our studies suggest that PYK2 is a common downstream effector of ErbB and
IL8 receptors, and that PYK2 integrates their signaling pathways through a positive feedback loop to potentiate
breast cancer invasion. Hence, PYK2 could be a potential therapeutic target for a subset of
breast cancer patients.