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Nat Cell Biol. 2015 Mar;17(3):217-27. doi: 10.1038/ncb3118. Epub 2015 Feb 23.

Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice.

Author information

1
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.
2
Princess Margaret Cancer Centre/University Health Network, Toronto, Ontario M5G 2M9, Canada.
3
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.
4
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.

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.

PMID:
25706237
DOI:
10.1038/ncb3118
[Indexed for MEDLINE]

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