P38 delta MAPK promotes breast cancer progression and lung metastasis by enhancing cell proliferation and cell detachment

The protein p38 mitogen-activated protein kinase (MAPK) delta isoform (p38 delta) is a poorly studied member of the MAPK family. Data analysis from The Cancer Genome Atlas database revealed that p38 delta is highly expressed in all types of human breast cancers. Using a human breast cancer tissue array, we confirmed elevation in cancer tissue. The breast cancer mouse model, MMTV-PyMT (PyMT), developed breast tumors with lung metastasis; however, mice deleted in p38 delta (PyMT/p38 delta(-/-)) exhibited delayed primary tumor formation and highly reduced lung metastatic burden. At the cellular level, we demonstrate that targeting of p38 delta in breast cancer cells, MCF-7 and MDA-MB-231 resulted in a reduced rate of cell proliferation. In addition, cells lacking p38 delta also displayed an increased cell-matrix adhesion and reduced cell detachment. This effect on cell adhesion was molecularly supported by the regulation of the focal adhesion kinase by p38 delta in the human breast cell lines. These studies define a previously unappreciated role for p38 delta in breast cancer development and evolution by regulating tumor growth and altering metastatic properties. This study proposes MAPK p38 delta protein as a key factor in breast cancer. Lack of p38 delta resulted in reduced primary tumor size and blocked the metastatic potential to the lungs.