Biomarker Translation: A Breast Cancer Case Study

Biomarker translation is the holy grail of proteomic studies of disease. Around the middle of 2011, researchers from the Walter and Eliza Hall Institute in Melbourne, Australia announced a promising new prognostic marker for breast cancer. Researchers found that Bcl-2 proteins are able to protect cells after they have been damaged by chemotherapy drugs and prevent cancer cells from dying. They tested a new drug ABT-737, showing that it is able to neutralize the Bcl-2 proteins in cancer cells and may be a new way to treat this particularly aggressive class of breast cancer.¹ There is an overall growing interest in biomarkers because of their potential clinical applications.

At the same time, there are thousands of publications identifying biomarkers of disease; however, only a fraction of these make it to clinical use. Biomarker translation relies heavily on a feedback loop to validate them in a clinical setting and make sure that they carry enough sensitivity and specificity. Successful translation requires close collaboration among investigators identifying biomarkers and clinicians in biomarker translation.^{2, 3}

Villeneuve et al.⁴ performed a mass spectrometry analysis (Thermo Scientific) of the Bcl-2 family of proteins to define its mode of action. This crucial step in biomarker translation was able to link Bcl-2 to an apoptotic pathway. They were also able to identify a Bcl-2 interacting protein, galectin-7 (Gal7), a member of a protein family that has previously been shown to have cellular functions, including regulation apoptosis. Additionally, researchers found that Gal7 mitochondrial localization is partly dependent on Bcl-2 expression. This study provides additional insight into the way that Bcl-2 functions in the cell and exerts its effect on internal pathways.

In the case of breast cancer, we know that there are a number of different types and that the triple negative form, named as such because they test negative for oestrogen, progesterone, and HER2 receptors, cannot be treated with conventional chemotherapy or hormone therapy. The Bcl-2 protein is promising because it is commonly over expressed in breast cancer and a number of studies have confirmed it as a suitable potential drug target. The Blc-2 protein appears to be a success story for biomarker translation for now, with recent in vivo studies confirming that ABT-737 is sensitizing breast cancers to chemotherapy.⁵ With the attention of the media having and the large number of recent publications devoted to understanding Bcl-2 in breast cancer, it is likely that this will be a successful example of biomarker translation.

References

1. Walter and Eliza Hall Institute of Medical Research, http://www.wehi.edu.au

2. Wagner, P.D. and Srivastava, S. (2012) ‘New paradigms in translational science research in cancer biomarkers‘, Translational Research, 159 (4), (pp. 342-253)

3. Frangogiannis, N.G. (2012) ‘Biomarkers: hopes and challenges in the path
from discovery to clinical practice‘, Translational Research, 159 (4), (pp. 197-204)

4. Villeneuve, C., et al. (2011) ‘Mitochondrial proteomic approach reveals galectin-7 as a novel BCL-2 binding protein in human cells‘, Molecular Biology of the Cell, 22 (7), (pp. 999-1013)

5. Oakes, S.R., et al. (2012) ‘Sensitization of BCL-2-expressing breast tumors to chemotherapy by the BH3 mimetic ABT-737‘, Proceedings of the National Academy of Science, 109 (8), (pp. 2766-2771)