SATB1 is a nuclear protein well known for its crucial role in regulating gene expression during the differentiation and activation of T cells, making it a key player in the immune system.
But SATB1 has now revealed a darker side: it is an essential contributing factor in the most aggressive forms of breast cancer.
Breast cancer cells need SATB1 to become metastatic; metastasis -- the stage when cells break away from the original tumor and spread to other parts of the body -- is the final step of solid tumor progression and is the most common cause of death in cancer patients.
"In breast tumors, SATB1 reprograms the genome to change the expression of hundreds of genes, promoting tumor growth and metastasis," says Terumi Kohwi-Shigematsu, a scientist in the Life Sciences Division of the Department of Energy's Lawrence Berkeley National Laboratory who, with her colleagues, discovered SATB1 and has since investigated its many functions. She says, "SATB1's role in breast cancer is a new paradigm for the way tumors progress."
Kohwi-Shigematsu, working with Berkeley Lab's Hye-Jung Han and Yoshinori Kohwi, and with Jose Russo of the Fox Chase Cancer Center in Philadelphia, found that when SATB1 is detected in a breast tumor, the cancer is highly likely to progress or recur.
Moreover, by introducing SATB1 into otherwise nonmetastatic breast cancer cells, invasive tumors can be induced in mice; conversely, removing SATB1 from metastatic cells not only abolishes metastasis and tumor growth in mice but also returns cells to their normal appearance in vitro. The researchers have published these and other findings in the March 13, 2008 issue of Nature.
How SATB1 works
Kohwi-Shigematsu and Kohwi originally identified a class of DNA sequences they called base-unpairing regions (BURs), a finding that led Kohwi-Shigematsu's group to the discovery of "special AT-rich sequence binding protein 1" (SATB1). SATB1 binds to BURs in double-stranded DNA by recognizing the BURs' distinctive phosphate-backbone structure. BURs contain unusual sequence contexts that readily unzip to expose DNA's individual strands.
As a nuclear architectural protein, SATB1 forms what Kohwi-Shigematsu calls a "3 D chickenwire network" inside the nucleus of the cell. SATB1 anchors chromosomes to its cage-like structure by tethering the BURs in the target genes, thus serving as a kind of "glue" for these genes. SATB1 folds and remodels the chromatin -- the intertwined DNA and proteins that form chromosomes -- into new shapes, bringing even distant parts of the genome together for coordinated control of gene expression and regulation.
SATB1 also globally regulates histone status in the chromatin by recruiting histone-modifying enzymes to the target-gene loci. Histones are the proteins around which DNA in chromatin is wound like thread on a spool; histone status renders DNA sequences accessible or inaccessible for transcription.
Early on, SATB1's ability to regulate gene expression was identified as critical to T-cell development. Although Kohwi-Shigematsu and her colleagues have found several other cell types that use SATB1 to reshape chromatin and regulate gene expression in a similar way, SATB1 is not expressed in all cells. SATB1 seems particularly important in cells which must change their function -- as do many progenitor cells, including the thymocytes that turn into T cells. And as cancerous cells must do to turn into metastatic cells.
"Hye-Jung Han of our group started by looking at two dozen breast-cell lines, including normal human epithelial cells" -- epithelial cells are the kind that form the linings of hollow glands in the breast -- "and both nonmetastatic and metastatic breast cancer cells," Kohwi-Shigematsu says. "Only the metastatic cells expressed SATB1, with the most aggressive breast cancer cells showing the highest levels of the protein."
The researchers examined over 2,000 human primary breast cancer tissue samples for which clinical follow-up studies were available. The highest levels of SATB1 were in samples from patients whose survival times had been shortest; patients whose tumor samples had no SATB1 expression generally had longer survival times.
The analysis showed that a high level of SATB1 expression by itself is an excellent indicator of poor prognosis -- independent of whether breast cancer cells have already metastasized to the lymph nodes at the time of diagnosis.
SATB1 takes command
The reason why SATB1 is a good prognostic marker is because SATB1 drives breast cancer cells to become invasive, as revealed by both in vitro and in vivo studies.
The researchers performed in vitro studies of highly metastatic cell lines, reducing SATB1 expression through the use of shRNAs, "short-hairpin-interfering" RNAs, that dramatically reduced the invasive capacity of these cells and also reduced their capacity for unattached growth -- a necessity if metastasizing cancer cells are to travel through the blood and lymph vessels.