Molecule related to inflammation promotes cancer growth, linked to poor prognosis.
Investigators have discovered a protein that may enable one of the deadliest forms of breast cancer to grow and spread quickly. The team, led by Antoine Karnoub, PhD, an assistant professor of pathology at the Cancer Center Beth Israel Deaconess Medical Center (BIDMC), hopes the findings published in the journal Science Signaling will lead to new diagnostics and treatments.

Basal–like breast cancer is diagnosed more frequently in unsuspecting young women and is usually detected after it has reached advanced stages. Existing chemotherapy and radiation treatments are successful in treating some affected patients, but those who do not benefit have poor outcomes.

Previous work has indicated that certain reactions – what’s known as the phosphoinositide 3–kinase (PI3K) pathway – are overactive in basal–like breast cancer. The PI3K pathway helps regulate a variety of important cellular functions – including growth, migration, and metabolism – and is often hijacked by cancer cells. However, blocking the pathway hasn’t shown a benefit for patients with basal–like breast cancer because the cancer cells can compensate by activating other pathways that feed off of the PI3K pathway. Therefore, identifying molecules that mediate the PI3K pathway may lead to more effective therapeutics for basal–like breast cancer.

With this in mind, Karnoub and colleagues examined genes that are regulated by over–activated PI3K in cells. They conducted gene expression experiments of breast cancer cells with over–active PI3K compared with non–cancerous cells. The scientists found that certain genes involved in inflammatory reactions are tightly under the control of the PI3K pathway, with the most noticeable being the pentraxin–3 (PTX3) gene. The gene codes for the PTX3 protein, which plays a number of important roles in local and systemic inflammation. The team verified the connection of PTX3 to the PI3K pathway by examining PTX3 expression in the presence of PI3K pathway inhibitors, and by associating PTX3 expression to PI3K activation status in clinical specimens.

When the researchers analyzed the function of PTX3 in breast cancer cells, they found that PTX3 provides cells with the capacity to grow as spheres, and it stimulates the expression of cell markers that are tied to tumor formation. In addition, PTX3 expression is essential for the growth–promoting activities of 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 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.”

Furthermore, when the scientists examined cancer cells from patients, expression of PTX3 served as a powerful prognostic indicator for worse survival.

In addition to potentially helping investigators develop new methods for diagnosing basal–like breast cancer earlier, when there is a better chance for curative treatment, the findings may also lead to new therapies that are based on PTX3 inhibition.

However, many unanswered questions remain. The most important from a basic science point–of–view concerns the mechanisms behind PTX3’s actions.

“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,” Karnoub noted. “We also don’t know why PTX3 is so exclusively expressed in these basal–like breast cancers and not other subtypes.”

It’s also unclear if targeting PTX3 would be catastrophic for tumor cells, or if they would be able to