Nucleolin and ErbB2 inhibition reduces tumorigenicity of ErbB2-positive breast cancer cells

Significance

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.

About the author

A PhD student in the Direct PhD Track Program at Tel-Aviv University. She has received her BSc from the Research focused Honors’ Biology program in the Faculty of Life Sciences in Tel Aviv University in 2013, and started her PhD in Prof. Pinkas-Kramarski’s lab later that year. During her time in the lab she has been a part of several cancer research projects, and was involved in study of cancer physiology, signaling pathways and autophagy, as well as in examination and development of personalized anti-cancer therapeutics. Mrs. Wolfson’s current research focuses on the role of nucleolin in ErbB2 ligand-independent signaling in ErbB2-positive tumors. An interaction that was found to be associated with poor prognosis and increased disease progression in ErbB2-positive breast cancer patients as part of this study. This study involves the examination of the physiological roles and oncogenic significance of this interaction, as well as the identification of novel therapeutic targets and the development of personalized treatment strategies, based on these targets.

About the author

Head of the Neurobiology Department at the Faculty of Life Sciences, Tel Aviv University, Director of the Prajs–Drimmer Institute for the Development of Anti–Degenerative Drugs, Tel-Aviv University.

Prof. Pinkas-Kramarski has a longtime experience in cell biology research, particularly regarding cell signaling pathways and metabolic processes. Prof. Pinkas-Kramarski did her PhD studies in biochemistry at Tel-Aviv University. She has completed her Post-Doctoral studies at the Weizmann Institute of science in Israel, in the field of molecular cell biology, specifically studying the combinatorial signaling of the ErbB family of receptor tyrosine kinases. Upon completion of her Post-Doctoral studies, Prof. Pinkas-Kramarski received a position at the Neurobiology Dep. in Tel Aviv University, and in 2016 was appointed as a full-Professor.

The Pinkas-Kramarski lab, active since 1997, mainly focuses on studying pathways that regulate cell proliferation and viability. Her laboratory study signaling mediated by the ErbB family of receptor tyrosine kinases. Her research lead to identification of new oncogenic interaction between ErbB receptors and nucleolin leading to enhanced tumor cell growth. Her studies demonstrated that nucleolin could activate the receptor in a ligand-independent manner. Other research projects performed in the lab include the study of autophagy at the molecular level by exploring the role of Beclin 1 protein, and at the physiological level in cancer and neurodegeneration. In addition, the Pinkas-Kramarski lab specializes in exploration of novel treatment strategies as part of the personalized medicine approach, namely development of specific-target drugs, and the design and testing of efficient drug combinations.

Reference

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.

Go To Cell Death and Disease 9(2018)