Metastasis of cancer cells is the final step in solid-tumor progression, and the most common cause of death in cancer patients. One culprit implicated in an aggressive form of breast cancer is special AT-rich sequence binding protein 1, or SATB1.
“SATB1 is a nuclear protein that normally plays a critical role in regulating gene expression during thymocyte differentiation and activation of T cells,” said Terumi Kohwi-Shigematsu, Ph.D., scientist in the life sciences division of the DOE’s Lawrence Berkeley National Laboratory. “However, in breast cancer cells, once SATB1 becomes expressed, it reprograms expression of a multitude of genes to promote tumor growth and metastasis.”
Dr. Kohwi-Shigematsu said that SATB1’s role in breast cancer represents a new paradigm. “We believe this is a new model of gene regulation leading to tumor progression. A key question we are investigating is how SATB1 alters expression of so many genes. In our studies, the expression of more than 1,000 genes is altered by SATB1 expression in breast cancer cells. SATB1 in the nucleus has a unique architectural distribution, onto which its target genes are anchored and assembled with chromatin-modifying enzymes and transcription factors, thus providing a regulatory network.
“Therefore, such a regulatory network must play a critical role in regulating the epigenetic status of chromatin and gene expression. Similar to the case found in activated T cells, it is also likely that in breast cancers, SATB1-targeted genes collect into intra- or even interchromosomal loci to form chromatin loops so that they can be coregulated. What we are seeing is an emerging link between chromatin remodeling enzymes, epigenetics, and cancer.”
Understanding the mechanisms used by SATB1 could provide a new diagnostic and prognostic marker as well as a therapeutic target for breast cancer. “Most companies are interested in targeting proteins on the cell surface. In the future, however, an effective strategy might be developed to target proteins in the nucleus such as SATB1. By discovering which signaling pathways are important for SATB1 activation we may be able to target them for therapeutics as well,” Dr. Kohwi-Shigematsu concluded.