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Due to PAD4's known roles in DNA compaction and NET formation, Wang and colleagues examined how PAD4 expression in breast cancer cells impacts the structure of DNA-protein networks known as chromatin.
They found that activation of PAD4 in 4T1 cells led to the modification of histones and the release of chromatin fibers outside the cell. The released chromatin fibers formed NET-like structures, which the authors referred to as cancer extracellular chromatin networks (CECNs).
Further experiments demonstrated that PAD4 was required for the formation of CECNs, both in cell culture and in allograft tumors in mice.
By comparing the growth and spread of allograft tumors that did or did not express PAD4, the authors observed that PAD4-expressing tumors grew significantly faster in mice and had significantly more metastases in the lungs, which are the usual site of 4T1 metastasis.
Further experimentation revealed that PAD4 promoted the growth of metastatic tumors after cancer cells had reached the lungs.
"Together, our results demonstrate that PAD4 expression in breast cancer cells promotes CECN formation, primary tumor growth, and lung metastasis in mice," said Wang. "The exact mechanism by which PAD4 exerts these effects is something we are actively investigating." Understanding how PAD4 promotes tumor growth and metastasis could help researchers develop drugs to target this process, explained Wang.
"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.
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," Wang added. Wang and colleagues are also interested in investigating if PAD4 contributes to progression or metastasis of other cancers.
A limitation of the study is that it was performed using a single cell line. Thus, studying additional cell types and human breast cancer samples will be needed to understand the prevalence of CECN formation and PAD4's role in the process, Wang noted. Source:
American Association for Cancer Research Journal reference:
Shi, L. et al . (2020) Endogenous PAD4 in Breast Cancer Cells Mediates Cancer Extracellular Chromatin Network Formation and Promotes Lung Metastasis. Molecular Cancer Research. doi.
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