On the Horizon

Unraveling the role of PTX3 in basal-cell cancer may lead to important diagnostic, therapeutic options

Liz Meszaros, MDLinx | February 28, 2017

In patients with basal-like breast cancer, pentraxin-3 (PTX3), an inflammatory mediator that helps the immune system fight bacteria and viruses, may play an important role in supporting the growth of cancer cells—in which it is present as well, according to researchers from Beth Israel Deaconess Medical Center (BIDMC), Boston, MA. Their findings are published in the journal Science Signaling.

Basal-like breast cancers

Inhibition of PTX3--which seems to facilitate the growth of cancer cells--may provide new diagnostic and therapeutic avenues for basal-like breast cancers.

Previously, researchers have shown that the phosphoinositide 3-kinase (PI3K) pathway is overactive in basal-like breast cancer. This pathway regulates many vital cellular functions, such as growth, migration, and metabolism, and is often “hijacked” by cancer cells. Blocking the pathway, however, has not been beneficial in these patients, because the cancer cells activate other pathways feeding off of the PI3K pathway.

Antoine Karnoub, PhD, an assistant professor of pathology at the Cancer Center Beth Israel Deaconess Medical Center (BIDMC), and fellow researchers studied the genes regulated by over-activated PI3K in cells through gene expression experiments in breast cancer cells with overactive PI3K and compared them with non-cancerous cells.

The PI3K pathway, they found, maintains tight control over certain genes that are involved in inflammatory reactions, most notably, the PTX3 gene, which codes for the PTX3 protein and which in turn comes into play in local and systemic inflammation. Using PI3K pathway inhibitors, they assessed PTX3 expression, and demonstrated the connection of PTX3 to the PI3K pathway. They also did so through associating PTX3 expression with PI3K activation status.

In breast cancer cells, Dr. Karnoub and colleagues analyzed the function of PTX3, which they found gives cells the capacity to grow as spheres, stimulates the expression of cells markers tied to tumor formation, and are necessary for growth-promoting activities via the PI3K pathway.

“We found that this inflammatory mediator, which otherwise helps the immune system fight bacteria and viruses, is abundantly produced by cancer cells and that it exerts critical activities in supporting their growth,” said Dr. Karnoub. “We have also established that this mediator is an important component of the tumor-driving pathway that is activated in these subtypes of breast cancers.”

These researchers also found that the expression of PTX3 in cancer cells was a strong prognostic indicator for worse survival.

New therapies based on the inhibition of PTX3 may, in the future, provide new avenues for the diagnosis of basal-like breast cancer, one of the deadliest forms of cancer that is usually only detected after reaching advanced stages. Poor outcomes are seen in patients in whom chemotherapy and radiation are unsuccessful.

But, according to Dr. Karnoub, many unknowns remain about PTX3, including the possibility that cancer cells could—as they do under other circumstances such as PI3K pathway blockade—develop ways to work around its inhibition.

“Indeed, we still do not know how it acts on the cancer cells, and whether it exerts additional activities on neighboring non-cancer cells within tumors,” he noted. “We also don’t know why PTX3 is so exclusively expressed in these basal-like breast cancers and not other subtypes.”

This work was supported by the Howard Hughes Medical Institute International Student Research Fellowship, American Cancer Society Postdoctoral Fellowship, NIH grant R35CA197684, NCI Breast SPORE P50-CA58223-09A1, RO1-CA148761, NIH grant CA177910, Sidney Kimmel Foundation, Komen Foundation for the Cure, and the Department of Defense Breast Cancer Research Program.