title: Age-related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors.
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.
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
authors.forename: Fanny A
authors.initials: FA
authors.lastname: Pelissier
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Garbe
authors.affiliation: Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Badriprasad
authors.initials: B
authors.lastname: Ananthanarayanan
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Masaru
authors.initials: M
authors.lastname: Miyano
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Department of Comparative Biochemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: ChunHan
authors.initials: C
authors.lastname: Lin
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
authors.forename: Tiina
authors.initials: T
authors.lastname: Jokela
authors.affiliation: Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Martha R
authors.initials: MR
authors.lastname: Stampfer
authors.affiliation: Center for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, Norway.
authors.forename: James B
authors.initials: JB
authors.lastname: Lorens
authors.affiliation: Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: malabarge@lbl.gov.
authors.forename: Mark A
authors.initials: MA
authors.lastname: LaBarge
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D002454:Cell Differentiation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000502:physiology; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human