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

Nature Cell Biology volume 17, pages 217–227 (2015)Cite this article

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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.

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Figure 1: Spontaneous expansion of mammary stem cell pool in ageing Timp1/Timp3 doubly deficient mammary glands.
Figure 2: Overabundance of basal cells changes mammary tissue stoichiometry in aged Timp1−/−/Timp3−/− mice.
Figure 3: Notch activation in Timp1−/−/Timp3−/− glands leads to increased luminal progenitors.
Figure 4: Timp1−/−/Timp3−/− glands have accelerated functional differentiation and return to normal cell stoichiometry post-involution.
Figure 5: Mass spectrometry of basal cells identifies abnormal extracellular and cytoskeletal protein repertoires.
Figure 6: Prevention of age-related mammary tissue regression when stem and progenitor pools are expanded.
Figure 7: Adult Timp1−/−/Timp3−/− mice do not have increased breast cancer susceptibility.

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Acknowledgements

The authors thank Marco A. Di Grappa, S. R. Narala and H. Fang for technical assistance, Cedric Blanpain (Brussels, Belgium) for providing the wholemount immunofluorescence protocol and P. Joshi for critical review of the manuscript. H.W.J. was awarded a Canadian Breast Cancer Foundation doctoral fellowship, and this research was supported by funding from the Canadian Breast Cancer Foundation and the Canadian Cancer Society Research Institute to R.K.

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Authors and Affiliations

  1. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9, Canada

    Hartland W. Jackson, Ankit Sinha, Thomas Kislinger & Rama Khokha

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

    Hartland W. Jackson, Paul Waterhouse, Ankit Sinha, Thomas Kislinger, Hal K. Berman & Rama Khokha

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

    Hal K. Berman & Rama Khokha

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Contributions

H.W.J. and R.K. designed the study and wrote the manuscript; H.W.J. and P.W. carried out limiting dilution assay cell transplants; A.S. and T.K. carried out mass spectrometry proteomics; H.K.B. directed mitosis scoring, advised on mammary tissue ageing and classified mammary tumours; H.W.J. carried out and analysed all other experiments; R.K. directed the study.

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Correspondence to Rama Khokha.

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Integrated supplementary information

Supplementary Figure 4 FACS analysis of luminal and basal cell populations across the family of Timp deficient mammary glands and with age in Timp1−/−/Timp3−/− glands.

a, Representative FACS plots of luminal (CD24+CD49flo) and basal (CD24+CD49fhi) populations generated from single and compound Timp mutant glands as indicated. b, Total lin−(ter119−CD45−CD31−) mammary cell number after collagenase digestion from individual and compound 6-month-old Timp deficient mammary glands (mean ± s.e.m., one-way ANOVA; n = 3 WT, 4 T1, 4 T3, 5 T1T3 ∗∗∗P < 0.0001, 4 T1T2T4 mice). c, Quantification of total luminal (red), basal (blue) and stromal (grey) (CD24−CD49f−) populations in 6-month-old adult mammary glands (mean ± s.e.m., one-way ANOVA; n = 3 WT, 4 T1, 4 T3, 5 T1T3, 4 T1T2T4 mice; Basal T1T3 p = 0.0002, Stromal T1T3 p = 0.0378). Solid bars represent Timp1−/−/Timp3−/− glands. d, Quantification of total luminal (CD24+CD49flo), basal (CD24+CD49fhi) and stromal (CD24−CD49f−) in 9-week or 6-month old WT or Timp1−/−/Timp3−/− mice, as well as their further segregated luminal differentiated (CD49floCD61+), luminal progenitor (CD49floCD61+) and basal (CD49fhiCD61+) (e) cell populations (mean ± s.e.m., two-way ANOVA with Tukey’s multiple comparisons test; 9 weeks n = 3 WT, 7 T1T3 mice and 6 months n = 6 WT, 5 T1T3 mice ∗p = 0.0400,∗∗∗P < 0.0001). f, Representative FACS plots of WT and Timp1−/−/Timp3−/− Sca1 and CD49b stained luminal cells. g, Enumeration of total Sca1 and CD49b segregated luminal cells as well as basal (CD24+ CD49fhi, blue) cells in 6-month-old mammary glands (mean ± s.e.m., Student’s T-test; n = 3, Luminal Progenitor p = 0.0080, Basal p = 0.0504). h, Measurement of serum hormones in 6-month-old WT and Timp1−/−/Timp3−/− mice (mean ± s.e.m., Student’s T-test; n = 4 WT, 3 T1T3 mice).

Supplementary Figure 5 Comparison of cell type specific marker gene expression from total gland and FACS-purified cell populations.

a, qRT-PCR expression in total mammary homogenates (black, mean ± s.e.m., n = 3 mice) and flow cytometry sorted luminal differentiated (CD49floCD61−, yellow), luminal progenitor (CD49floCD61+, red), basal (CD24+CD49fhiCD61+, blue) and stromal (CD24−CD49f−, grey) cell populations (coloured, mean ± s.e.m., n = 4 WT, 6 T1T3 mice). Cell markers used include ER & PR for luminal differentiated hormone receptor positive cells, Keratin 8, Keratin 18 for luminal cells, Keratin 5, Keratin 14 & p63 for basal cells and Fibroblast activated protein (FAP) for stromal fibroblasts. b, Representative immunofluorescence image of PR (red), Keratin 5 (green) and DAPI (blue) completed in n = 3 mice (scale bar 10 μm).

Supplementary Figure 6 Wnt and TGFβ signalling in WT and Timp1−/−/Timp3−/− mammary glands.

a, Quantification of Wnt target genes cMyc and TCF7 by qRT-PCR in FACS-purified cell populations (luminal differentiated, CD49floCD61+, yellow; luminal progenitor, CD49floCD61+, red; basal, CD24+CD49fhiCD61+, red; stromal, CD24−CD49f−, grey; mean ± s.e.m., two-way ANOVA with Šidák’s multiple comparisons test; n = 3 mice). b, Representative immunofluorescent images of β-catenin (red), Keratin 5 (green), and DAPI nuclear stain (blue) in WT and Timp1−/−/Timp3−/− mammary glands (n = 3 mice, scale bar 20 μm (top) and 5 μm (bottom). c, Immunoblotting of total mammary gland lysates for unphosphorylated (active) β-catenin, total β-catenin and β-actin as loading control; d, qRT-PCR expression of TGFβ target gene Wnt5a and TGFβ1 ligand in FACS-purified cell populations (mean ± s.e.m., two-way ANOVA with Šidák’s multiple comparisons test; n = 3 mice). e, Immunoblots of phosphorylated SMAD2/3, total SMAD and loading control β-actin. f, ELISA for activated TGFβ ligand per 150 μg of total mammary gland lysate (mean ± s.e.m., Student’s T-test; n = 3 WT, 4 T1T3 mice).

Supplementary Figure 7 Mammary luminal cell populations during gestation and after involution or ovariectomy.

Representative FACS-plots and quantification (mean ± s.e.m., Student’s T-test) of luminal differentiated (CD49floCD61−, yellow), and luminal progenitor (CD49fhiCD61+, red) (a,c,e), or hormone receptor positive (CD49b−Sca1+, yellow) and luminal progenitor (CD49b+Sca1−, red) populations (b,d,f) in WT and Timp1−/−/Timp3−/− adult mammary glands at 16.5 dpc (ab; n = 3 WT, 4 T1T3 mice), post-involution (c,d; n = 3 mice), or after ovariectomy (e,f; n = 5 WT, 4 T1T3 mice).

Supplementary Figure 8 Unaltered integrin levels, increased gelatinase activity and divergent mitotic orientation in Timp1−/−/Timp3−/− mammary glands.

a, Protein intensity comparison of integrin family proteins detected by mass spectrometry (mean ± s.e.m., Student’s T-test; n = 3 mice). b, Gelatin zymography of mammary tissue lysates indicates increased MMP9 as well as increased mature/active MMP2 in Timp1−/−/Timp3−/−glands. c, H&E images of representative mitotic orientations, scale bar 20 μm. d, Radial histograms of mitotic spindle angles relative to the adjacent tissue boundary (lumen or matrix). e, Histograms of the average absolute number of mitosis per 1 mm2 grouped by angle of division per genotype (mean ± s.e.m., two-way ANOVA with Šidák’s multiple comparisons test; n = 5 mice). f, Quantification of luminal (red) or basal (blue) mitosis as a percentage of total mammary ductal cells in mice >6 months of age (mean ± s.e.m., Student’s T-test; n = 5 mice, ∗p = 0.0140) g, Representative immunofluorescence of phosho-histone H3 positive mitotic DNA (green) and the SMA positive basal compartment (red) completed in n = 10 mice; scale bar 20 μm, inset scale bar 5 μm.

Supplementary Table 1 Scoring of mitotic orientation in adult estrus-staged mammary glands.
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Supplementary Table 2 Antibodies.
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Supplementary Table 3 RT-PCR Primers.
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Supplementary Video 1

Z stack image of basal Timp1−/−/Timp3−/− mitotic cell. Movie of rotating confocal microscopy Z stack of immunofluorescence stained Timp1−/−/Timp3−/− mammary gland. DAPI (blue), SMA (red), and phospho-Histone H3 (green). (AVI 73 kb)

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Jackson, H., Waterhouse, P., Sinha, A. et al. Expansion of stem cells counteracts age-related mammary regression in compound Timp1/Timp3 null mice. Nat Cell Biol 17, 217–227 (2015). https://doi.org/10.1038/ncb3118

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