It's relatively easy to run studies that explore the association between gene expression and cancer prognosis. Those studies, however, don't always paint a clear picture of what the genes do—many of them may be effect (instead of cause) or simply innocent bystanders that are simply caught up in the changes caused by cancer progression. A new study that appears in today's issue of Nature not only describes a strong correlation between the expression of a gene and the ability of breast cancer cells to metastasize, but also presents evidence that indicates the gene plays a key role in regulating the process.
The researchers started with 24 breast cancer cell lines and found that one gene, SATB1, was expressed in all of them. That link held up in cells taken directly from breast cancers, and, in a large population study with tissue from 1,000 patients, SATB1 showed a very significant correlation with longer survival times.
The authors then switched from correlation to experimental evidence. Invasive cancer cells were made to express interfering RNAs that blocked SATB1 expression. The loss of SATB1 had a variety of effects, including reducing the cells' proliferation and inducing them to form duct-like structures that normally appear in the breast. The cells themselves went from a spiky shape that sent out many invasive processes to one that was relatively rounded and, by one measure, was 85 percent less invasive. The researchers also injected cancer cells, with and without the SATB1 RNAi, into immunocompromised mice. The ability to invade and form tumors correlated with the cells' expression of the gene. The same held when a complementary experiment was done: cells that normally fail to establish themselves in mice became tumor forming when engineered to express SATB1.
How can one gene have such a profound impact? Some hints come from what we know about the role of SATB1 in the immune system. There, the protein helps link the distant areas of the chromosome that contain a number of genes involved in the immune response. Once brought in proximity, the genes can all be regulated in a coordinated manner.
To see whether this happens in cancer cells, the researchers did gene expression profiling of cells with and without SATB1. They found that its expression regulates nearly 900 genes, split nearly equally between those activated and shut down. Of the set of genes identified, about 35 percent had already been known to be associated with a poor cancer prognosis. Chromatin immunoprecipitation experiments (called "ChIP") showed that SATB1 attached directly to the DNA near many of these genes, and its presence led to changes in the chromosome packaging that are associated with differences in gene regulation (primarily histone acetylation).
Overall, the authors have built a compelling case that SATB1 is not only associated with aggressive cancers, but that its expression can directly produce the coordinated changes in gene expression that may switch cells into an aggressive state. The study leaves some key questions unanswered—it's not clear how SATB1 can alter chromosomes to turn genes both on and off—but it clearly indicates that finding answers to these questions is going to be very important.
Nature, 2008. DOI: 10.1038/nature06781