Researchers from the Stowers Institute for Medical Research have uncovered new details about several proteins implicated in tumor growth and metastasis, opening a potential avenue for the development of treatments for diseases such as breast cancer. The research focuses on the tumor-suppressing function of Smad4, a transcription factor protein normally involved in the regulation of cell growth processes. Its function is often turned off in breast cancer, which allows tumors to grow and metastasize. In a new report, published online this October 23 in the journal Science Advances, the researchers found that BRK/PTK6, a non-receptor protein tyrosine kinase, binds to and leads to Smad4 breakdown. The study was done using human cell lines, including a panel of breast cancer cell lines. In breast cancer, Smad4 function is often impaired, which sets the stage for tumors to grow and spread to additional sites in the body.
The BRK kinase is present in more than 85% of breast cancer tumors; it works like an oncogene (a gene that has the potential to cause cancer when mutated or abnormally expressed) in breast cancer. In their previous work published last January this year, scientist studied the influence of estrogens on the expression of BRK protein in breast cancer. They examined BRK expression in 120 breast tumor samples and 29 breast cancer cell lines to explore the positive correlation between BRK and the expression of the estrogen receptor (ERα). Using immunohistochemistry, RT-PCR, and protein analysis (immunoblotting), scientists demonstrated that estrogen induces BRK gene and protein expression in ER+ breast cancer cells. Over-expression of ERα in the ER-negative breast cancer cell line increased BRK expression.
Moreover, BRK presence in malignant cells is regulated by ERα signaling, since ER antagonists (tamoxifen and fulvestrant) reduce the expression of BRK in ER+ breast cancer cells. Finally, they demonstrated that the overall survival of ER-positive breast cancer patients is poor when their cancers express high levels of BRK. This means that BKR may become a feasible and stable marker of breast cancer aggressiveness. Researchers believes that these findings are an important step in understanding how cancer works and would like to find other molecules that work with BRK to degrade Smad4. If they further increase understanding of this protein network, these insights may reveal new targets for metastatic cancer intervention. The research already suggests that treatments against BRK kinase may help retain Smad4 function, therefore reducing or stopping tumor growth.
But this is already half of the path, since researchers have already identified some inhibitors of BRK. In 2017, a joint team from Harvard University and Xiamen University of China discovered new molecules that happen to be BRK inhibitors. One of them, XMU-MP2 appeared very specifi, reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Also two years ago it was resolved the molecular structure of BRK complexed with dasatinib, a tyrosine kinase inhibitor already used to cure leukemia. Even earlier, in 2014, a team from the University of Louisiana identified compounds derived from marine organisms that appeared to target BRK and FAK, another kinase involved in breast cancer metastasis.
More efforts, especially if laboratory will be willing to cooperate, will lead to a final crush of this major deathbringer called breast cancer.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Miah S et al., Lukong KE. BMC Cancer. 2019 Jan 16; 19(1):78.
Ito K, Park SH et al. NPJ Breast Cancer. 2017 Nov 17; 3:45.
Thakur MK et al. B.B. Res Commun. 2017; 482(4):1289-1295.
Jiang J et al., Deng X. Cancer Res. 2017 Jan 1; 77(1):175-186.
Sallam AA et al. Org Biomol Chem. 2014 Jul; 12(28):5295-303.