Investigating a Protein’s Role in Recovery From Breast Cancer

by Suzanna Engman

Why do Hispanic women have a 40 percent lower rate of breast cancer incidence than other women, yet have a higher mortality rate as a result of this disease? Zarixia Zavala Ruiz, professor and biochemist at the University of Puerto Rico, Río Piedras Campus is experimenting with a protein that may help provide an answer to this question. At U. Mass Medical School, where she was a postdoctoral researcher, she began to work with the lymphocyte activation gene-3 (LAG-3), which had just recently been identified. Now Zavala Ruiz is characterizing the structure of the protein that LAG-3 transcribes and examining its role in Puerto Rican women with breast cancer.

Preliminary research links breast cancer survival with the presence of the LAG-3 protein, expressed only on activated T-cells. The “T” in T-cell refers to the thymus, the organ in which these white blood cells mature. T-cells are important in fighting infection as part of the adaptive immune system, which tailors the body’s immune response to specific pathogens. They find and destroy trespassers such as bacteria, viruses, and foreign tissues. They also produce cytokines, substances that cause T-cells to proliferate and direct responses in other immune cells, for example in B cells, which express antibodies.

The ability of T-cells to recognize a specific antigen (the trespasser that is stimulating antibody production) is determined by proteins on the cell surface—the receptors. The receptor and the antigen fit together like pieces of a puzzle only when their shapes match perfectly. The cell’s proteins, produced by genes such as LAG-3, seem to be responsible for the number and specificity of T-cell receptors.

“There’s a French study, done about four years ago, that says breast cancer patients with detectable levels of LAG-3 protein in their blood serum usually get better and survive. Without detectable levels, the patients have a worse prognosis. I want to know if Hispanic women are expressing reasonable levels of LAG-3 proteins. If we’re able to detect LAG-3 proteins, will Hispanic women with breast cancer get better? And if we can’t detect it, what is their prognosis?”

Zavala Ruiz hopes her studies of the structure, functions, and interactions of LAG-3 proteins will answer these questions. “We know that the soluble form of LAG-3 protein binds specifically to the molecule called MHC II that exists on antigen presenting cells (APCs). APCs are responsible for displaying foreign antigens bound to MHC II molecules and presenting them to T-cells.”

Some of the most potent APCs in our immune system are the dendritic cells. Scientists have found that soluble LAG-3 proteins can activate dendritic cells, and this occurs when soluble LAG-3 protein interacts with MHC II.

Zavala Ruiz obtains her LAG-3 protein samples from insect cells and bacteria, which are comparable to LAG-3 protein in humans. “We’re doing basic research to figure out the mechanism of action and what the protein looks like in three dimensions. This can give us a good idea about how it functions and how to alter it, if we need to, so that it carries out other functions or more specific functions.”

In addition to this basic biochemical research, Zavala Ruiz and oncologist Reynold López will collaborate with M.D. Anderson Cancer Center in Houston to investigate the connection between LAG-3 protein and cases of Puerto Rican women with breast cancer. The projected five-year study, to begin in June 2009, will look at LAG-3 protein expression in blood samples, ideally samples from breast cancer biopsies.

“We think we can use this as a prognosis of how breast cancer patients will respond to a treatment and whether they are going to survive.”

Zarixia Zavala Ruiz in the Protein X-ray Crystalography Facility with the X-ray Defractometer, the only instrument of its kind in the Caribbean. X-rayed protein crystals produce a defraction pattern that can help identify the structure of a protein, such as the LAG-3, which may be important in breast cancer recovery.