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  • Home
  • Targeting EDI3: A Potential Therapeutic Strategy for HER2-Positive Breast Cancer

A Novel Single-Cell Culture Approach for Tracking Phenotypic Heterogeneity in vSMCs
September 1, 2023
“I loved the whole conference”: an interview with the winners of the AMSBIO ISSCR 2023 Travel Grant
July 28, 2023

Targeting EDI3: A Potential Therapeutic Strategy for HER2-Positive Breast Cancer

HER2-positive breast cancer is a highly aggressive subtype characterized by the overexpression of the human epidermal growth factor receptor 2 (HER2). While HER2-targeted treatments have significantly improved patient outcomes for this form of cancer, acquired and inherent resistance to treatment remains a challenge, prompting investigations into alternative therapeutic targets.

A team of researchers led by Dr. Rosemarie Marchan at the Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund in Germany conducted a study exploring the clinical relevance of EDI3, a glycerophosphodiesterase involved in choline metabolism, in HER2-positive (HER2+) breast cancer – utilising a custom-made monoclonal antibody against EDI3 from AMSBIO. The study begins to unravel the mechanistic role of EDI3 in breast cancer development, its regulation by HER2 signalling, and its potential as a therapeutic target.

We tested many commercially available antibodies over the years, with little to no success. We have also contracted other companies to create an antibody for us, but again with limited success. Therefore, we are very thankful that we were able to get a really great antibody from AMSBIO many years ago, and since there is only a limited amount left, it is really more precious than gold.

Dr. Rosemarie Marchan of the Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the TU Dortmund in Germany

Key Findings:

High expression of EDI3 in ER-HER2+ tumours:

Through analysis of breast cancer datasets, the researchers found that EDI3 mRNA expression was significantly higher in HER2+ tumours compared to HER2- tumours, with the oestrogen receptor negative (ER-) HER2+ subtype showing the highest expression. Immunohistochemistry on tissue microarrays using a custom EDI3 antibody from AMBSIO confirmed that ER-HER2+ tumours exhibited higher EDI3 protein expression than other subtypes. In Western blots, the antibody also highlighted greater EDI3 protein expression in ER-HER2+ cell lines compared to cell lines of other subtypes, providing further evidence of the relationship between EDI3 and HER2 status.

Regulation of EDI3 by HER2 Signalling:

To investigate the mechanisms regulating EDI3 expression in HER2+ breast cancer, Dr. Marchan and her team silenced HER2 using siRNA which resulted in decreased EDI3 expression. Inducing HER2 expression, on the other hand, led to an increase in EDI3. Inhibiting targets downstream of HER2 activation, namely GSK3β and mTORC1, reduced EDI3 expression, suggesting their involvement in regulating EDI3. Furthermore, downstream transcription factors such as HIF1α, CREB, and STAT3 were identified as potential regulators of EDI3 expression, indicating a complex regulatory network involved in controlling EDI3 levels. These findings suggest EDI3 expression is induced by HER2+ signalling and modulated by mTORC1 and GSK3β, however further investigations are required to fully unravel the mechanism underlying its regulation.

Figure 1. (A) Immunohistochemistry on a human breast cancer tissue microarray (TMA) using a custom-made anti-EDI3 antibody from AMSBIO (clone 3B8G3), showing examples of negative staining (left) and strong EDI3 positivity (right). (B) Elevated EDI3 protein levels in ER-HER2+ SKBR3 cells visualized by immunocytochemistry; Figure adapted from Keller, M., Rohlf, K., Glotzbach, A. et al. Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth. J Exp Clin Cancer Res 42, 25 (2023). https://doi.org/10.1186/s13046-022-02578-w.

Increased Sensitivity of ER- HER2+ Cells to EDI3 Inhibition

Silencing EDI3 significantly reduced cell viability in the ER-HER2+ subtype but had minimal impact on ER+HER2+ cells. Interestingly, combining EDI3 knockdown with HER2 inhibition using either lapatinib or trastuzumab, significantly enhanced the efficacy of HER2-targeted therapy in ER-HER2+ cells. More importantly, in cells resistant to lapatinib, the combined inhibition of both EDI3 and HER2 did not lead to an enhanced effect on viability compared to silencing EDI3 alone, suggesting EDI3 as a potential alternative target to overcome HER2-targeted therapy resistance.

In Vivo Efficacy of EDI3 Inhibition:

Marchan et al. investigated the impact of targeting EDI3 on tumour growth in mice, either alone or in combination with HER2 inhibition. They found that inhibiting EDI3 with dipyridamole resulted in decreased tumour growth, particularly in ER-HER2+ cells. Moreover, inducible silencing of EDI3 using doxycycline led to a significant reduction in tumour volume and weight, further supporting the potential of targeting EDI3 as a therapeutic strategy for targeting ER-HER2+ breast cancer.

Conclusion

The work of Dr. Marchan and her team at the Leibniz Research Centre for Working Environment and Human Factors (IfADo) highlights the potential of targeting EDI3 as a therapeutic strategy for HER2+ breast cancer. Their work also presents the promising possibility of combining HER2 -targeting drugs with additional treatments to address resistance mechanisms, thereby enhancing standard therapies or providing alternatives for patients who are resistant to current treatments. As researchers continue to unravel the intricacies of resistance mechanisms, it is hoped that such discoveries will lead to improved treatment options and better outcomes for patients with HER2+ breast cancer.

 

AMSBIO is proud to have supplied the team of talented researchers with a custom monoclonal antibody used to identify EDI3 in their investigations. We offer a thorough and high-quality service for producing customized monoclonal antibodies tailored to your target antigen. Simply provide us with the target sequence, and we will generate monoclonal antibodies of exceptional quality, characterized by high specificity and affinity.

Further reading

Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth.

Keller, M., Rohlf, K., Glotzbach, A., Leonhardt, G., Lüke, S., Derksen, K., Demirci, Ö., Göçener, D., AlWahsh, M., Lambert, J., Lindskog, C., Schmidt, M., Brenner, W., Baumann, M., Zent, E., Zischinsky, M.-L., Hellwig, B., Madjar, K., Rahnenführer, J., … Marchan, R. (2023).

Journal of Experimental & Clinical Cancer Research, 42(1). https://doi.org/10.1186/s13046-022-02578-w

This study was supported by the German Cancer Aid (70114035)

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