title: Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice.
abstract: Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age tissues atrophy. We show that cell-extrinsic factors maintain the adult stem cell pool during ageing and dictate tissue stoichiometry. Mammary stem cells spontaneously expand more than 11-fold in virgin adult female mice lacking specific genes for TIMPs, the natural metalloproteinase inhibitors. Compound Timp1/Timp3 null glands exhibit Notch activation and accelerated gestational differentiation. Proteomics of mutant basal cells uncover altered cytoskeletal and extracellular protein repertoires, and we identify aberrant mitotic spindle orientation in these glands, a process that instructs asymmetric cell division and fate. We find that progenitor activity normally declines with age, but enriched stem/progenitor pools prevent tissue regression in Timp mutant mammary glands without affecting carcinogen-induced cancer susceptibility. Thus, improved stem cell content can extend mouse mammary tissue lifespan without altering cancer risk in this mouse model.
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Hartland W
authors.initials: HW
authors.lastname: Jackson
authors.affiliation: Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Waterhouse
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Ankit
authors.initials: A
authors.lastname: Sinha
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: 1] Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Hal K
authors.initials: HK
authors.lastname: Berman
authors.affiliation: 1] Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada [2] Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada [3] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000172:deficiency / Q000235:genetics*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000235:genetics*
chemical_list: D003598:Cytoskeletal Proteins; D051880:Receptors, Notch; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3