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

• Published in: Oncogene Vol. 36; no. 47; pp. 6649 - 6657
• Main Authors: Wada, M, Canals, D, Adada, M, Coant, N, Salama, M F, Helke, K L, Arthur, J S, Shroyer, K R, Kitatani, K, Obeid, L M, Hannun, Y A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.11.2017; Nature Publishing Group
• Subjects: 631/67/1347; 631/80/79/2027; Animals; Apoptosis; Breast - pathology; Breast cancer; Breast Neoplasms - pathology; Care and treatment; Cell Adhesion; Cell adhesion & migration; Cell Biology; Cell growth; Cell Proliferation; Complications and side effects; Data processing; Development and progression; Disease Progression; Female; Focal adhesion kinase; Gene expression; Genetic aspects; Genomes; Health aspects; Human Genetics; Humans; Internal Medicine; Kinases; Lung cancer; Lung Neoplasms - secondary; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; MAP kinase; MCF-7 Cells; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 13 - genetics; Mitogen-Activated Protein Kinase 13 - metabolism; Oncology; original-article; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein kinase; Protein kinases; Proteins; Tissue Array Analysis; Tumor proteins; Tumors; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.274

The protein p38 mitogen-activated protein kinase (MAPK) delta isoform (p38δ) is a poorly studied member of the MAPK family. Data analysis from The Cancer Genome Atlas database revealed that p38δ 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 p38δ (PyMT/ p38δ −/− ) exhibited delayed primary tumor formation and highly reduced lung metastatic burden. At the cellular level, we demonstrate that targeting of p38δ in breast cancer cells, MCF-7 and MDA-MB-231 resulted in a reduced rate of cell proliferation. In addition, cells lacking p38δ 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 p38δ in the human breast cell lines. These studies define a previously unappreciated role for p38δ in breast cancer development and evolution by regulating tumor growth and altering metastatic properties. This study proposes MAPK p38δ protein as a key factor in breast cancer. Lack of p38δ resulted in reduced primary tumor size and blocked the metastatic potential to the lungs.