Tumor Metastasis: Pieces of the Puzzle

When engaging in discussion about the role of animals in scientific research I am frequently frustrated by how polarized the debate can be, with anti-vivisectionists often claiming that animal research has made little or no contribution to advancing medical science, while occasionally defenders of animal research seem to imply that animal research alone was responsible for said advances. The reality is a little more complex with many approaches, some using animals, some not, being crucial to the process. A procedure that uses animals might confirm and extend the findings of an in vitro experiment, and then in its turn be verified and enlarged upon by a clinical study in man. A study published in Nature this week by Dr Terumi Kohwi-Shigematsu and colleagues (1), and picked up by the Independent newspaper, provides a neat illustration of this process in action. Their work determined that a protein called SATB1, previously identified as a key factor in driving the expression of genes required for immune system T-cell development, was also a key player in breast cancer metastasis.

Breast cancer still kills over 10,000 women every year in the UK, the majority when the cancer spreads from the breast to other tissues.Dr. Kohwi-Shigematsu’s team started by identifying a protein called SATB1 that was found in cell lines derived from metastatic breast tumour cells but not in cell lines derived in non-metastatic cells. A screen of samples from over 1,000 breast cancer patients found that higher levels of SATB1 in tumour biopsies were associated with a worse prognosis. These results indicated that higher levels of SATB1 were associated with metastasis, but not that these higher levels caused metastasis. After all the higher SATB1 levels could have been a result of cells becoming metastatic, so they next used RNA interference (RNAi) to silence SATB1 gene expression in vitro in a metastatic cell line and found that this caused the cells to grow more slowly and adopt the characteristics of non-metastatic cells.At this point they were ready to see what effect different levels of SATB1 expression had on metastasis in a mouse breast cancer model. In a series of tests they observed that breast cancer cells expressing SATB1 were far more likely to metastasize and form tumours in other tissues, and that this metastasis could be blocked by RNAi targeting SATB1, results that confirmed the key role played by SATB1 in metastasis. They didn’t stop there though, and returned to in vitro microarray studies which demonstrated that SATB1 affects the activity of over 1,000 genes, notably increasing expression of metastasis-associated genes while downregulating tumour-suppressor genes.

So where it goes from here? Perhaps the expression of SATB1 will in future be used as a criterion when deciding whether a patient would benefit from more aggressive chemotherapy, or maybe SATB1 will itself become a target for drugs designed to block metastasis. It may even turn out that a gene whose expression is altered by SATB1 is a more tempting target for new anti-cancer drugs. What is certain is that with this very thorough piece of work Dr Kohwi-Shigematsu’s team has opened a promising new avenue for cancer research.

Paul Browne


1) Han H.-J. et al. “SATB1 reprogrammes gene expression to promote
breast tumour growth and metastasis.” Nature. Vol. 452(7184), Pages
187-93 (2008) PubMed: 18337816.