Dachshund Depletion Disrupts Mammary Gland Development and Diverts the Composition of the Mammary Gland Progenitor Pool

• Published in: Stem cell reports 2019-01, Vol.12 (1), p.135-151
• Main Authors: Jiao, Xuanmao, Li, Zhiping, Wang, Min, Katiyar, Sanjay, Di Sante, Gabriele, Farshchian, Mehdi, South, Andrew P., Cocola, Cinzia, Colombo, Daniele, Reinbold, Rolland, Zucchi, Ileana, Wu, Kongming, Tabas, Ira, Spike, Benjamin T., Pestell, Richard G.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; breast cancer; Cells, Cultured; DACH; Eye Proteins - genetics; Eye Proteins - metabolism; Female; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Humans; Keratin-5 - genetics; Keratin-5 - metabolism; mammary gland; Mammary Glands, Human - cytology; Mammary Glands, Human - growth & development; Mammary Glands, Human - metabolism; Mice; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - metabolism; Rats; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; SARA; Smad Proteins - genetics; Smad Proteins - metabolism; stem cells; TGF-β; Transforming Growth Factor beta - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.11.010

DACH1 abundance is reduced in human malignancies, including breast cancer. Herein DACH1 was detected among multipotent fetal mammary stem cells in the embryo, among mixed lineage precursors, and in adult basal cells and (ERα+) luminal progenitors. Dach1 gene deletion at 6 weeks in transgenic mice reduced ductal branching, reduced the proportion of mammary basal cells (Lin− CD24med CD29high) and reduced abundance of basal cytokeratin 5, whereas DACH1 overexpression induced ductal branching, increased Gata3 and Notch1, and expanded mammosphere formation in LA-7 breast cells. Mammary gland-transforming growth factor β (TGF-β) activity, known to reduce ductal branching and to reduce the basal cell population, increased upon Dach1 deletion, associated with increased SMAD phosphorylation. Association of the scaffold protein Smad anchor for receptor activation with Smad2/3, which facilitates TGF-β activation, was reduced by endogenous DACH1. DACH1 increases basal cells, enhances ductal formation and restrains TGF-β activity in vivo. •Dach1 is expressed in mammary gland fetal stem cells and adult luminal cells•Dach1 expands mammary gland basal/myoepithelial cells•Dach1 induces post-natal mammary gland ductal formation•Dach1 retrains TGF-β activity in the mammary gland in vivo DACH1 abundance, is reduced in human malignancies, including breast cancer. In this article, Dr. Pestell and his colleagues showed that DACH1 is expressed in multipotent mammary gland fetal stem cells and both the adult basal and ERα+ luminal cells, promotes mammary gland stem cell and basal/myoepithelial cell expansion, promotes mammary gland ductal branching, and restrains TGF-β action in the pubertal mammary gland.