Developing therapies for disease is kind of like trying to put together a series of incredibly complex puzzles. Scientists collect lots of “puzzle pieces”, in the form of data, through experiments in the lab and clinic or by reading up on other researchers’ results. Each piece gives researchers a tidbit of insight but the breakthroughs rely on connecting the pieces to see the whole picture.

This is how the story has played out for a research team studying breast cancer at the Medical College of Georgia at Augusta University. Reporting last Friday in the American Journal of Pathology, the researchers connected the origin of several cell types present in breast tumor tissue to a common mutant precursor stem cell that is likely responsible for helping tumors thrive.

This finding was made possible by the identification of a mutation in the gene, GT198, that may not only provide a diagnostic tool for early breast cancer detection but also a totally new target for therapies. This is hopeful news for the one in eight women in the U.S. who will develop invasive breast cancer during their lifetime.

The GT198 gene carries the code for a protein that activates other genes in the presence of the hormone, estrogen. In its mutated form, GT198 protein no longer relies on estrogen to function and instead get stuck in the “on” position. Analyzing 249 human breast cancer tissues and 11 healthy samples, the researchers detected GT198 protein in breast tumor stromal tissue but not in the healthy samples.

Anatomy of the breast. The cells of the stroma produce connective tissue and fat which support the lobules and ducts, structures that produce and deliver milk.

The stroma (meaning “mattress” in Greek) contains various cell types, some of which are responsible for producing fat and connective tissue, that provide structural support for the milk producing glands and ducts in the breast. But the presence of mutated GT198 in the tumor stromal tissue is thought to sabotage the cells into providing a favorable microenvironment for tumor growth. For instance, in one cell culture experiment, the team showed that mutant GT198 but not normal GT198 leads to increased angiogenesis, or new blood vessel growth, and fat production – activities associated with cancer initiation.

The presence of the mutant GT198 in not just one but several of the tumor stromal cell types, strongly suggests that they all come from the same stem cell or progenitor cell. Among the cells harboring the GT198 mutation, the pericytes – found in the stromal capillary blood vessels – also have significant amounts of CD44, a marker for progenitor cells, the progeny of stem cells. So the team hypothesizes that mutant pericytes are the precursor cells that give rise to the other mutant cells found in breast cancer stromal tissue.

GT198 protein (brown staining) is specifically detected in various cell types found in breast cancer stroma. Tumor cells outside the stroma (panel K) don’t have GT198. Blue color indicates DNA.
Am J Pathol 2016, 186: 1-11

In an interview with MedicalResearch.com, senior author Kan Lo described the implications of these findings:

Dr. Kan Lo

“In breast cancer, the progenitor cells are mutated leaving mutant stromal cell offspring with altered activities to induce tumor. Mutant stem or progenitor cells may have longer lifespan than their mutant descendants so that they can fuel cancer growth for years. Eliminating those mutant progenitors at the source, at least in theory, will efficiently stop cancer.”

 

One way of getting rid of those mutant progenitors could be by developing drugs that block the GT198 protein. Another exciting use of GT198 is as a diagnostic. Since the mutant stromal cells are important for providing the right conditions for tumor growth, it’s likely that they are present in the early stages of the cancer. So testing for the presence GT198 could be a tool for catching breast cancer early.

Sounds like we need to put together a few more puzzles before scientists can understand the full story of GT198 and breast cancer.