Format

Send to

Choose Destination
Cell Rep. 2014 Jun 26;7(6):1926-39. doi: 10.1016/j.celrep.2014.05.021. Epub 2014 Jun 5.

Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors.

Author information

1
Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
2
Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
3
Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
4
Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Comparative Biochemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
5
Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
6
Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: malabarge@lbl.gov.

Abstract

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 <30 years were exposed to a physiologically relevant range of matrix elastic modulus (stiffness). Increased stiffness causes a differentiation bias towards myoepithelial cells while reducing production of luminal cells and progenitor maintenance. Lineage representation in progenitors from women >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.

PMID:
24910432
PMCID:
PMC4122253
DOI:
10.1016/j.celrep.2014.05.021
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center