Overexpression of ErbB2 receptors is often found in different malignancies with approximately 30% of patients being ErbB2 positive in breast cancer. Previous studies have reported that the physical interaction between ErbB2 and nucleolin results in uncontrolled cell proliferation and increased resistance to apoptosis. Nucleolin stimulates the activation of ErbB2, which results in an increase in cell tumorigenicity. Indeed, the presence of nucleolin and ErbB2 positive tumors in cancer patients increases the risks associated with the disease and reduces survival rate. Recently, it was discovered that treatment with anti-nucleolin G-rich oligonucleotide (GroA) significantly impaired the growth and viability of ErbB2-positive tumors in vitro. However, the inhibitory role of GroA treatment alone and in combination with ErbB2 inhibition on the growth and viability of ErbB2-positive tumors has not been examined in vivo.
Recently, Professor Ronit Pinkas-Kramarski and colleagues at Tel-Aviv University in Israel demonstrated the inhibitory effect of GroA treatment on the growth and ErbB2 activation in breast cancer xenografts. The authors also examined the effect of GroA and tyrphostin AG-825 (AG-825) treatment on the growth and viability of ErbB2-positive tumor cells. Their work is now published in the research journal: Cell Death and Disease.
The authors observed that the overexpression of nucleolin caused a significant increase in the phosphorylation of Erk and ErbB2, the ErbB2 protein levels, the growth and volume of nucleolin expressing tumors in SKBR3 ErbB2 positive breast cancer cells. In addition, they found that GroA treatment caused a significant decrease in the mean volume of the tumors, inhibited the activation of Erk and ErbB2 and signiﬁcantly decreased the physical interaction between ErbB2 and nucleolin. Also, GroA treatment reduced the viability of SKBR3 and MCF7 human breast cancer cell lines but exhibited no effect on the non-cancerous, human breast tissue cell line, MCF10A. The authors’ findings showed that MCF7 cells were more sensitive to treatment with GroA compared to SKBR3 cells.
Furthermore, the co-treatment of SKBR3 and MCF7 cells with GroA and AG-825 caused a signiﬁcant decrease in cell colony formation compared to cells that were either untreated or treated with a single drug. There was indeed pronounced reduction in ErbB2 receptor-phosphorylation with the combined GroA and AG-825 treatment.
The GroA and AG-825 co-treatment also caused a blockade of migration with reduced number of SKBR3 and MCF7 cells that could invade the Cultrex basement membrane, compared to cells that were untreated or treated with GroA or AG-825.
Ronit Pinkas-Kramarski and colleagues’ study resulted in the identification of a novel target for the development of anti-cancer therapeutics. The intricate findings by the Tel-Aviv University researchers will stimulate further studies on the clinical importance of interference with ErbB2–nucleolin complex and the use of GroA as a suitable drug for breast cancer treatment.
Wolfson, E., Solomon, S., Schmukler, E., Goldshmit, Y., and Pinkas-Kramarski, R. Nucleolin and ErbB2 inhibition reduces tumorigenicity of ErbB2-positive breast cancer, Cell Death and Disease 9(2018), 47.