Abstract
ErbB2, a member of the ErbB family of receptor tyrosine kinases, is an essential player in the cell’s growth and proliferation signaling pathways. Amplification or overexpression of ErbB2 is observed in ∼30% of breast cancer patients, and often drives cellular transformation and cancer development. Recently, we have shown that ErbB2 interacts with the nuclear-cytoplasmic shuttling protein nucleolin, an interaction which enhances cell transformation in vitro, and increases mortality risk and disease progression rate in human breast cancer patients. Given these results, and since acquired resistance to anti-ErbB2-targeted therapy is a major obstacle in treatment of breast cancer, we have examined the therapeutic potential of targeting the ErbB2–nucleolin complex. The effect of the nucleolin-specific inhibitor GroA (AS1411) on ErbB2-positive breast cancer was tested in vivo, in a mouse xenograft model for breast cancer; as well as in vitro, alone and in combination with the ErbB2 kinase-inhibitor tyrphostin AG-825. Here, we show that in vivo treatment of ErbB2-positive breast tumor xenografts with GroA reduces tumor size and leads to decreased ErbB2-mediated signaling. Moreover, we found that co-treatment of breast cancer cell lines with GroA and the ErbB2 kinase-inhibitor tyrphostin AG-825 enhances the anti-cancer effects exerted by GroA alone in terms of cell viability, mortality, migration, and invasiveness. We, therefore, suggest a novel therapeutic approach, consisting of combined inhibition of ErbB2 and nucleolin, which has the potential to improve breast cancer treatment efficacy.
Highlights
The four members of the ErbB tyrosine kinase receptor (RTK) family, ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4), are cell surface receptors, involved in cell proliferation, survival, and growth signaling
We found that co-treatment of breast cancer cell lines with GroA and the ErbB2 kinase-inhibitor tyrphostin AG-825 enhances the anti-cancer effects exerted by GroA alone in terms of cell viability, mortality, migration, and invasiveness
By analyzing data from breast cancer patients, obtained from the Cancer Genome Atlas (TCGA) network, we have found that patients who present with both nucleolin- and ErbB2-positive tumors are at greater disease risk and exhibit lower survival rates compared to ErbB2positive patients
Summary
The four members of the ErbB tyrosine kinase receptor (RTK) family, ErbB1 (EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4), are cell surface receptors, involved in cell proliferation, survival, and growth signaling. Apart from ErbB2, which is an orphan receptor, the ErbBs are activated following ligand binding, which leads to receptor dimerization, and trans-autophosphorylation of tyrosine residues in their cytoplasmic tails[1]. Despite being an orphan receptor, ErbB2 is the preferred dimerization partner among its family members, and its association with other ErbBs enhances signaling intensity and dimer stability[2,3]. The involvement of nucleolin in cell signaling and proliferation is not limited to its nuclear roles, as it shuttles between the nucleus, the cytoplasm and the plasma membrane, and has a wide range of cytoplasmic and membrane activities.
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