Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors

• Published in: Cell reports (Cambridge) 2014-06, Vol.7 (6), p.1926-1939
• Main Authors: Pelissier, Fanny A., Garbe, James C., Ananthanarayanan, Badriprasad, Miyano, Masaru, Lin, ChunHan, Jokela, Tiina, Kumar, Sanjay, Stampfer, Martha R., Lorens, James B., LaBarge, Mark A.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Adult; Age Factors; Cell Differentiation - physiology; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; Humans; Mammary Glands, Human - cytology; Mammary Glands, Human - metabolism; Mechanotransduction, Cellular - physiology; Middle Aged; Phosphoproteins - metabolism; Stem Cells - cytology; Stem Cells - metabolism; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.05.021

Dysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelial aging for reasons not understood. Multipotent progenitors from women aged 55 years is unaffected by physiological stiffness changes. Efficient activation of Hippo pathway transducers YAP and TAZ is required for the modulus-dependent myoepithelial/basal bias in younger progenitors. In older progenitors, YAP and TAZ are activated only when stressed with extraphysiologically stiff matrices, which bias differentiation towards luminal-like phenotypes. In vivo YAP is primarily active in myoepithelia of younger breasts, but localization and activity increases in luminal cells with age. Thus, aging phenotypes of mammary epithelia may arise partly because alterations in Hippo pathway activation impair microenvironment-directed differentiation and lineage specificity. [Display omitted] •Mechanoresponse in multipotent human mammary progenitors is age dependent•The mechanosensing systems are equally active in young and old progenitors•Hippo pathway transducers YAP and TAZ exhibit age-dependent activation efficiencies•YAP localization changes with age in vivo In this study, Pelissier et al. use primary normal finite-lifespan human mammary epithelial progenitor cells to demonstrate that the Hippo pathway transducers YAP and TAZ are important myoepithelial/basal cell-fate determinants in premenopausal epithelia. However, during the aging process, the efficiency of YAP and TAZ activation decreases, and their activation in postmenopausal progenitors reveals a changed differentiation spectrum.