Cancer progressionCancer. The very word evokes an uneasiness in our health-obsessed culture … and, unfortunately, for good reason: malignant neoplasms (cancers) are responsible for more than 1 in every 5 deaths in the United States.1

First, a little background on cancer (skip to next paragraph for the news). Cancer is basically the proliferation of cells that shouldn’t proliferate. However, a ‘malignant’ neoplasm is additionally defined by proliferating cells that invade the surrounding tissue, causing an indistinct margin between normal cells and the neoplasm. Malignant tumors are contrasted by their benign counterparts, called ‘in situ’ tumors. In situ literally means ‘in place,’ and indicates a well-behaved neoplasm that sticks to itself. In situ tumors can, however, be precursors to malignant behavior. Malignant cancer cells, in addition to encroaching on the immediate surrounding tissue, may enter the blood vessels and lymphatics of the tissue and travel to other parts of the body like the liver, lungs and bone, where they will implant and seed a new colony of cancer cells (however, the colony is made up of the same tissue type as the primary tumor). This event is named metastasis.

The diagram on the right illustrates the accepted progression of healthy cells into cancer. A most interesting aspect to the process is that, while we understand how cancer cells arise — inactivation of tumor suppressor genes, DNA repair mechanisms going haywire, etc. — there is little consensus on why they arise. Many scientists believe that genetic mutations occur at random in some tumor cells, which then father a line of more “rare variant clones,”2 leading to observable metastases. Everyone agrees that genetic mutation is the root, but the reason for the genetic mutation is the subject of much debate and extensive research.

Fortunately, new findings help to shed a little light on possible sources of the genetic anomalies. This week’s Nature journal hosted an article that identifies the nuclear protein SATB1, a genomic organizer, as one likely cause of the upregulation of oncogenes and the downregulation of tumor suppressor genes in breast carcinoma. Likely, as in P<0.0001 for prognostic ability, likely.

[The SATB1 protein works] by recruiting chromatin remodelling/modifying enzymes and transcription factors13, 14 to genomic DNA, which it tethers via specialized DNA sequences highly potentiated for unpairing (base unpairing regions, or BURs). … In breast cancer cells, we find that once SATB1 is expressed, it coordinates expression of a large number of genes to induce metastasis.2

The SATB1 protein affects the regulation of over 1000 genes, making it a major player in the pathway to metastatic disease. The researchers also discovered that removing SATB1, “not only reverses metastatic phenotypes but also inhibits tumour growth”2 in aggressive breast cancers. The study comprised tests for the presence of SATB1 in human breast carcinoma, among other in vivo trials in mice and in vitro assays.

This discovery is novel because most cancer therapies attempt to combat the disease by minimizing the proliferation of the cancer cells. If a drug were made that targets the SATB1 protein for destruction, it could prevent the cells from developing into cancer at all. Of course, those are BIG “ifs,” and the next obvious question is, what leads to expression of SATB1? And down the carcinogenic rabbit hole we will continue.3

References:
(1) Final Draft of National Vital Statistics Report for 2004. CDC. 2007.
(2) SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis. Nature. 2008.
(3) The proverbial ‘rabbit hole’ is not, itself, a carcinogen; that wouldn’t make any sense. It was just a metaphor for the limitless depth of cancer understanding that we will pursue for the sake of saving lives. Ok, you know what, just forget I mentioned the rabbit hole.