WCM-Q research reveals underlying mechanisms of aggressive breast cancers
Researchers at Weill Cornell Medicine-Qatar (WCM-Q) have unveiled the key role played by a specific protein in the growth of the most aggressive, treatment-resistant forms of breast cancer.
A multi-institutional international study led by WCM-Q’s Dr. Lotfi Chouchane, Professor of Genetic Medicine, Microbiology and Immunology, found that the effects of a protein named STXBP6 are profoundly suppressed in triple-negative breast cancers (TNBCs), which are known to relapse early and tend to spread to other organs despite intensive treatments with surgery, chemotherapy and radiotherapy.
TNBCs account for around 15-20 percent of all breast cancers and are associated with the poorest patient outcomes. While many other forms of breast cancer can now be treated relatively successfully, there is currently no effective therapy that specifically targets TNBCs.
The study showed that the STXBP6 protein helps regulate and promote a natural cellular process called autophagy in which old and damaged cells are metabolized or ‘killed off’ in order to allow newer, healthier ones to grow. In cancer cells, autophagy suppresses tumor growth by inhibiting cancer cell survival and inducing cell death. When autophagy is suppressed in certain circumstances, cancer cells are more able to grow and proliferate.
Dr. Chouchane said: “There is a real need to develop new therapies that specifically target triple-negative breast cancers because they do not respond well to existing treatments. In this study, we were able to significantly enhance our understanding of the mechanisms that make TNBCs so aggressive and treatment-resistant, which we hope will provide targets for the development of effective new therapies for TNBCs to significantly improve patient outcomes.”
Triple-negative breast cancers are so called because the cancer cells do not have estrogen or progesterone receptors (which are targets for hormone-based therapies) and because they do not make a protein called HER2 (which is a target for antibody-based therapies) like some other forms of breast cancer.
The study, titled ‘STXBP6, reciprocally regulated with autophagy, reduces triple negative breast cancer aggressiveness’, also involved researchers at Weill Cornell Medicine in New York, Sidra Medicine and Hamad Medical Corporation in Doha, and the University of Groningen in the Netherlands. The research has been published in Clinical and Translational Medicine, a prestigious medical journal.
Dr. Chouchane explained that laboratory analysis showed the STXBP6 protein interacting with another protein, named SNX27, which is known to play a key role in autophagy. Furthermore, the researchers found that increased function of the STXBP6 protein significantly reduced TNBC cells’ migratory ability in cell-based in vitro experiments and also reduced tumor metastasis in mouse model-based in vivo testing. However, while autophagy appears to be heavily involved in maintaining cellular health and preventing tumor initiation, the process has a paradoxical dual role and in other circumstances can actually facilitate tumor survival, depending on a variety of factors such as cancer type and stage.
Dr. Chouchane added: “This multi-institutional study represents a new paradigm in our understanding of the role of autophagy in breast cancers, but it is an extremely complex and multifaceted process. We believe much more research is needed to understand in detail the role of autophagy throughout the many different development stages of cancer in order to create a new class of therapeutic strategies that are truly effective and safe.”
The study was supported by funding from the Biomedical Research Program of WCM-Q and by a grant from the Qatar National Research Fund (NPRP9-459-3-090).
Dr. Khaled Machaca, WCM-Q Professor of Physiology and Biophysics/Senior Associate Dean for Research, Innovations, and Commercialization, said: “This cutting-edge research paves the way for further investigations into the cellular processes that allow triple-negative breast cancers to resist current therapeutic strategies. Furthermore, the study provides extremely useful targets to aid the design of new, more effective cancer drugs in the future. These are very positive developments toward applying our research findings to improve healthcare delivery in Qatar in the long term.”