Regulation of Mammary Luminal Cell Fate and Tumorigenesis by p38α

• Published in: Stem cell reports 2018-01, Vol.10 (1), p.257-271
• Main Authors: del Barco Barrantes, Ivan, Stephan-Otto Attolini, Camille, Slobodnyuk, Konstantin, Igea, Ana, Gregorio, Sara, Gawrzak, Sylwia, Gomis, Roger R., Nebreda, Angel R.
• Format: Article
• Language: English
• Subjects: Animals; breast cancer; cell fate; Core Binding Factor Alpha 2 Subunit - metabolism; Female; luminal cell; mammary gland; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Mice; Mitogen-Activated Protein Kinase 14 - metabolism; MSK1; Neoplasm Proteins - metabolism; p38α; progenitor cell; Ribosomal Protein S6 Kinases, 90-kDa - metabolism; RUNX1
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.11.021

Mammary stem and progenitor cells are essential for mammary gland homeostasis and are also candidates for cells of origin of mammary tumors. Here, we have investigated the function of the protein kinase p38α in the mammary gland using mice that delete this protein in the luminal epithelial cells. We show that p38α regulates the fate of luminal progenitor cells through modulation of the transcription factor RUNX1, an important controller of the estrogen receptor-positive cell lineage. We also provide evidence that the regulation of RUNX1 by p38α probably involves the kinase MSK1, which phosphorylates histone H3 at the RUNX1 promoter. Moreover, using a mouse model for breast cancer initiated by luminal cells, we show that p38α downregulation in mammary epithelial cells reduces tumor burden, which correlates with decreased numbers of tumor-initiating cells. Collectively, our results define a key role for p38α in luminal progenitor cell fate that affects mammary tumor formation. •Luminal progenitor cell fate in the mammary gland is regulated by p38α•p38α controls the ER transcriptional program by modulating RUNX1•p38α regulates H3 phosphorylation at the RUNX1 promoter through the kinase MSK1•p38α promotes mammary tumorigenesis by maintaining luminal tumor-initiating cells del Barco Barrantes and colleagues use genetically modified mice to identify p38α as a key regulator of the fate of luminal progenitor cells of the mammary gland, which impinges on the ability of these cells to initiate tumors.