A protein that triggers aggressive breast cancer

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.