The bacteria-trapping protein that may provide a new target for tracking and treating breast cancer

Scientists at the Pennsylvania State University and Henan University in China have found a new protein marker that they say could potentially predict the progression of breast cancer or be targeted by drugs designed to treat the disease.

The protein, called PAD4, is key in the immune response against bacteria. The researchers found that its expression in cancer cells can also promote breast cancer metastasis in mice, according to a new study published in the journal Molecular Cancer Research.

PAD4 exists in abundance in neutrophils, a type of white blood cells. It mediates the formation of a loosened DNA and protein structure outside the cell called neutrophil extracellular traps (NETs). Normally, NETs trap and help kill bacteria. Recent studies have also found that NETs play a part in promoting cancer metastasis. But little was known about whether PAD4 can trigger a similar process in breast cancer cells.

That was what the Penn State and Henan team set out to study. “We were interested in learning if PAD4 expression in breast cancer cells could affect cancer biology, such as tumor growth and metastasis,” Yanming Wang, the study’s senior author, said in a statement.

So the team profiled gene expression in breast cancer cells from the Cancer Genome Atlas and Oncomine database. They found human breast cancer cells have higher PAD4 expression than do normal cells. In a triple-negative breast cancer cell line called 4T1, the researchers also observed even bigger PAD4 levels than what existed in other cell lines.

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Additional analysis showed that the activation of PAD4 in 4T1 cells also led to the release of chromatin fibers outside to form NET-like structures. The researchers called them cancer extracellular chromatin networks (CECNs).

CECN formation is dependent on PAD4, the team found, as treating the 4T1 cells with a pan-PAD inhibitor or knocking it out prevented the release of CECNs.

Wang and colleagues further assessed the role of PAD4 on tumor growth and metastasis. In mice injected with 4T1 breast tumors, those bearing the PAD4 marker saw significantly faster tumor growth and had much more metastases in the lungs than did animals without the marker.

To further test the idea that CECNs are indeed involved in metastasis, the researchers disrupted extracellular DNA including CECN in PAD4-knockout mice that were unable to release additional CECN. Although the procedure didn’t change the primary tumor, lung metastasis was significantly decreased, the team reported. Further investigation showed that PAD4 promoted tumor growth after cancer cells had reached the lungs.

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Despite the availability of many therapies, breast cancer is still the second leading cause of cancer-related deaths in women in the U.S. Many research groups are looking for new ways to block metastasis, which is a major cause of death.

Scientists at the Institute of Cancer Research recently found that blocking a protein kinase called MPS1 caused triple-negative breast cancer cells to divide so fast that they accumulated fatal errors. Researchers at the Fed Hutchinson Cancer Research Center showed that inhibiting proteins called integrins could target dormant estrogen receptor-positive breast cancer cells to prevent metastasis. And last year, a team at Boston Children’s Hospital used nanoparticles targeting the ICAM-1 molecule on triple-negative breast cancer cells to deliver a CRISPR system, which edited out a gene called Lipocalin 2 to slow tumor growth.

Wang believes PAD4 may offer a novel approach to tackling breast cancer. “While further investigation is needed, it is interesting to consider the possibility that PAD4 or CECNs could potentially be used as biomarkers to predict disease progression,” he explained. “Furthermore, therapies to inhibit PAD4 or eliminate CECNs could be explored as a method to reduce the risk of metastasis in patients with breast cancer.”

The team is now investigating the exact mechanism by which PAD4 affects CECN formation and drives tumor growth. The researchers are also studying additional cell types to better understand the prevalence of CECN formation and PAD4’s role.