Age-related dysfunction in mechano-transduction impairs differentiation of human mammary epithelial progenitors

Dysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelia aging for reasons not understood. Multipotent progenitors from women aged 55 years was unaffected by physiological modulus changes. Efficient activation of Hippo pathway transducers YAP and TAZ was required for the modulus-dependent myoepithelial/basal-bias in younger progenitors. In older progenitors YAP/TAZ were only activated when stressed by extra-physiologically rigid matrices, which biased differentiation towards luminal-like phenotypes. YAP was primarily active in myoepithelia of younger breast tissues, but activity increased in luminal cells with age. Thus aging phenotypes of mammary epithelia may arise partly because alterations in Hippo pathway activation affect the processes of progenitor differentiation and lineage specificity.