Abstract
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.
Highlights
Receptor tyrosine kinases (RTKs) of the ErbB family (ErbB1–4) are highly expressed in different breast cancer subtypes [1] and frequently contribute to breast cancer progression and metastasis [2]
To examine the role of PYK2 in ErbB receptors signaling in other breast cancer subtypes, we employed two estrogen receptor (ER) positive luminal A breast cancer cell lines, MCF7 and T47D, and an HER2-overexpressing cell line, SKBR3
In this study we show that PYK2 integrates EGFR/ HER2- and IL8-receptor signaling to potentiate cell invasion in breast cancer cells
Summary
Receptor tyrosine kinases (RTKs) of the ErbB family (ErbB1–4) are highly expressed in different breast cancer subtypes [1] and frequently contribute to breast cancer progression and metastasis [2]. Two classes of ligands activate the ErbB receptors; the EGF-like ligands and neuregulins (NRGs). EGF-like ligands induce the formation of ErbB1 (EGFR) homodimers or ErbB1/2 heterodimers, whereas NRGs bind directly to ErbB3 and/or ErbB4 and induce the formation of ErbB3 or ErbB4 homodimers as well as ErbB2/3 or ErbB2/4 heterodimers [4]. ErbB2 does not bind any known ligand [5], and ErbB3 has a crippled kinase domain lacking catalytic activity [6], and these two receptors actively function as heterodimers. ErbB2/3 heterodimer is known to induce strong mitogenic response [9], and ErbB2 in general, plays a critical role in heregulin (HRG)-induced breast cancer cell growth and migration [10]. Recent studies suggest that ErbB2 as well as EGFR can be trans-activated by cytokines including Interleukin-8 (IL8; CXCL8) [11], a neutrophil chemoattractant and an angiogenic factor with tumor promoting properties [12, 13]
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