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PIK3CAH1047R induces multipotency and multi-lineage mammary tumours

Nature volume 525, pages 114–118 (2015)Cite this article

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Abstract

The adult mouse mammary epithelium contains self-sustained cell lineages that form the inner luminal and outer basal cell layers, with stem and progenitor cells contributing to its proliferative and regenerative potential1,2,3,4. A key issue in breast cancer biology is the effect of genomic lesions in specific mammary cell lineages on tumour heterogeneity and progression. The impact of transforming events on fate conversion in cancer cells of origin and thus their contribution to tumour heterogeneity remains largely elusive. Using in situ genetic lineage tracing and limiting dilution transplantation, we have unravelled the potential of PIK3CAH1047R, one of the most frequent mutations occurring in human breast cancer5, to induce multipotency during tumorigenesis in the mammary gland. Here we show that expression of PIK3CAH1047R in lineage-committed basal Lgr5-positive and luminal keratin-8-positive cells of the adult mouse mammary gland evokes cell dedifferentiation into a multipotent stem-like state, suggesting this to be a mechanism involved in the formation of heterogeneous, multi-lineage mammary tumours. Moreover, we show that the tumour cell of origin influences the frequency of malignant mammary tumours. Our results define a key effect of PIK3CAH1047R on mammary cell fate in the pre-neoplastic mammary gland and show that the cell of origin of PIK3CAH1047R tumours dictates their malignancy, thus revealing a mechanism underlying tumour heterogeneity and aggressiveness.

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Figure 1: Mutant PIK3CA induces mammary cell plasticity.
Figure 2: Activation of PIK3CAH1047R leads to expression of basal- and luminal-lineage genes.
Figure 3: Expression of PIK3CAH1047R evokes multipotent stem-like cells.
Figure 4: The frequency of malignant tumour lesions is dictated by the cell of origin.

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Gene Expression Omnibus

Data deposits

Microarray data sets generated for this study have been deposited in the Gene Expression Omnibus under accession numbers GSE59870, GSE59872 and GSE65411.

Change history

  • 02 September 2015

    The spelling of author J.P.C. was corrected.

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Acknowledgements

The authors thank R. Thierry for help with image processing and quantification, S. Bichet and A. Bogucki for assistance with immunohistochemical staining, S. Thiry for assistance with the microarray analysis, L. Gelman, S. Bourke and M. Kirschmann for help with microscopy, C. Blanpain, B. Roska, B. Kinzel, J. Tchorz and A. Isken for providing mouse lines, and members of the Bentires-Alj group for their feedback. O.A. and R.D.C. were supported by National Cancer Institute grant U01 CA141582. Research in the laboratory of M.B.-A. is supported by the Novartis Research Foundation, the European Research Council (ERC starting grant 243211-PTPsBDC), the Swiss Cancer League, the Swiss National Foundation, and the Krebsliga Beider Basel.

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Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research (FMI), Basel, 4058, Switzerland

    Shany Koren, Linsey Reavie, Joana Pinto Couto, Duvini De Silva, Michael B. Stadler, Tim Roloff, Adrian Britschgi, Tobias Eichlisberger, Hubertus Kohler & Mohamed Bentires-Alj

  2. Swiss Institute of Bioinformatics, Basel, 4058, Switzerland

    Michael B. Stadler

  3. Department of Pathology, Center for Comparative Medicine, University of California Davis, Davis, 95616, California, USA

    Olulanu Aina & Robert D. Cardiff

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  1. Shany Koren
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Contributions

S.K. and M.B.-A. designed experiments, analysed the data and wrote the manuscript. L.R. contributed greatly to experimental design and data analysis. S.K. performed most of the experiments. L.R. and D.D.S. performed mammosphere cultures. L.R., D.D.S., J.P.C. and S.K. performed limiting dilution transplantations. M.B.S. and T.R. performed microarray data analysis. L.R. and J.P.C. quantified tumour immunohistochemistry. J.P.C. and A.B. isolated tumour RNA. A.B. performed immunoblotting. D.D.S. and T.E. provided technical assistance for several experiments. H.K. provided technical assistance for FACS experiments. O.A. and R.D.C. analysed histological tumour samples. All the authors discussed the data and participated in the preparation of the manuscript.

Corresponding author

Correspondence to Mohamed Bentires-Alj.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Scheme depicting mouse lines generated for lineage-tracing studies.

a, Lgr5-CreERT2(ref. 25) or K8-CreERT2(ref. 1) animals were crossed to transgenic lox-STOP-lox PIK3CAH1047R 16 and/or Tomato-reporter mice, generating Lgr5-CreERT2/Tomato, K8-CreERT2/Tomato, Lgr5-CreERT2/PIK3CAH1047R/Tomato and K8-CreERT2/PIK3CAH1047R/Tomato animals for lineage-tracing studies. Lgr5-CreERT2/Tomato and K8-CreERT2/Tomato animals were used as controls. b, Lgr5-CreERT2(ref. 25) and K8-CreERT2(ref. 1) animals were crossed to lox-STOP-lox PIK3CAH1047R(ref. 16) or PIK3CAWT(ref. 18) animals. Lgr5-CreERT2 and K8-CreERT2 animals were used as controls. Tamoxifen injection induces PIK3CAH1047R, PIK3CAWT and/or Tomato expression.

Extended Data Figure 2 Lgr5-CreERT2/Tomato and PIK3CAH1047R/Tomato labelling in the mammary nipple area.

a, Lgr5 expression in the nipple and distal area of Lgr5-CreERT2 glands (n = 3 mice). b, Tracing scheme. c, d, Representative images of mammary glands after 4 weeks tracing (n = 3 mice for each genotype). Scale bars, 2 mm, 100 μm (magnifications). e, Representative haematoxylin and eosin staining of an Lgr5-CreERT2/PIK3CAH1047R mammary gland with a tumour. Scale bar, 500 μm. LN, lymph node. f, Representative images, FACS plots and quantification of 4 days tracing (24 h after the last tamoxifen injection) (top: immunofluorescence: n = 3 mice; FACS: n = 5 technical replicates (each 1–2 pooled mice); bottom: immunofluorescence: n = 3 mice; FACS: n = 3 technical replicates (each 1 mouse)). Scale bars, 100 μm; 20 μm (magnifications). g, Representative FACS plots of 4-week tracing. h, Percentage of total Tomato-positive cells in the tracing experiments (Lgr5-CreERT2/Tomato: 4 days n = 5, 4 weeks n = 4, 8 and 13 weeks n = 3 technical replicates (each 1–2 pooled mice); Lgr5-CreERT2/PIK3CAH1047R/Tomato: 4 days n = 3, 4 weeks n = 3, 8 weeks n = 6 and 13 weeks n = 5 technical replicates (each 1–2 pooled mice)). i, Representative images of 7 days tracing (left n = 4 mice; right n = 2 mice). Scale bars, 100 μm, 50 μm (magnifications). Bar graphs show means ± s.e.m.; two-sided unpaired Student’s t-test; *P < 0.05; NS, not significant.

Extended Data Figure 3 Gating scheme for FACS experiments.

a–d, Representative FACS plots of K8-CreERT2/Tomato (a), K8-CreERT2/PIK3CAH1047R/Tomato (b), Lgr5-CreERT2/PIK3CAWT (c) and Lgr5-CreERT2/PIK3CAH1047R (d) animals 4 weeks after tamoxifen injection. The gating strategy shown illustrates the elimination of doublets, dead cells (DAPIHi), and white blood cells (CD45+) and the sorting of Tomato- or GFP-positive mammary epithelial subsets (basal CD24LoSca1−, luminal CD24HiSca1−; luminal CD24HiSca1+).

Extended Data Figure 4 K8-CreERT2/Tomato and PIK3CAH1047R/Tomato labelling in the mammary gland.

a, Scheme depicting timeline of tracing experiments. b, Representative images and FACS quantifications of K8-CreERT2/Tomato and K8-CreERT2/PIK3CAH1047R/Tomato mammary glands 4 days after tamoxifen (24 h after the last tamoxifen injection) (top: immunofluorescence: n = 5 mice; FACS: n = 7 technical replicates (each 1–2 pooled mice); bottom: immunofluorescence n = 3 mice; FACS: n = 3 technical replicates (each 1 mouse)). Scale bars, 100 μm, 20 μm (magnifications). c, Representative FACS plots of 4-week Tomato tracing. d, Percentage of total Tomato-positive cells in mammary glands (K8-CreERT2/Tomato: 4 days n = 7, 4 and 8 weeks n = 4, 13 weeks n = 5 technical replicates (each 1–3 pooled mice); K8-creERT2/PIK3CAH1047R/Tomato: 4 days n = 3, 4 and 8 weeks n = 4 and 13 weeks n = 3 technical replicates (each 1–2 pooled mice)). Bar graphs show means ± s.e.m. *P < 0.05; two-sided unpaired Student’s t-test.

Extended Data Figure 5 Tracing of GFP-positive mammary subsets.

a, Percentage of GFP-labelled cells in K8-CreERT2/PIK3CAH1047R versus K8-CreERT2/PIK3CAWT animals 4 days after tamoxifen (24 h after the last tamoxifen injection) (n = 3 technical replicates, 2 mice per genotype). b, d, Representative FACS plots and percentages of GFP-positive cells in mammary gland subsets and total mammary epithelial cells 4 and 8–11 weeks after tamoxifen. c, e, Bar graphs showing total numbers of GFP-positive cells and numbers of GFP-positive cells in basal (CD24LoSca1−) and luminal (CD24HiSca1−; CD24HiSca1+) subsets of Lgr5-CreERT2/PIK3CAH1047R (c) and K8-CreERT2/PIK3CAH1047R (e) mammary epithelial cells. b, c, 4 weeks: non-induced control n = 3, control n = 9, PIK3CAWT n = 3, PIK3CAH1047R n = 9 sortings with each 1–4 pooled mice; 8–11 weeks: non-induced control n = 3, control n = 3, PIK3CAWT n = 3, PIK3CAH1047R n = 4 sortings with each 1–4 pooled mice. d, e, 4 weeks: PIK3CAWT and PIK3CAH1047R n = 3 sortings with each 1–5 pooled mice; 8–11 weeks: PIK3CAWT n = 4, PIK3CAH1047R n = 5–6 sortings with each 1–4 pooled mice. Bar graphs show means ± s.e.m.; two-sided unpaired Student’s t-test; *P < 0.05; NS, not significant.

Extended Data Figure 6 Expression of PIK3CAH1047R induces Akt phosphorylation.

Immunoblot and quantification of lysates from K8-CreERT2 control, PIK3CAWT and PIK3CAH1047R mammary glands 4 weeks after tamoxifen for p110α, pAkt, Akt, pan-keratin and Erk2 (loading control). n = 3 mice per genotype. Protein levels were normalized to pan-keratin for normalization of epithelial content. Bar graphs depict fold change over control lysate. Bar graph shows means ± s.d.; two-sided unpaired Student’s t-test; *P < 0.006; NS, not significant.

Extended Data Figure 7 Expression of basal- and luminal-lineage genes in PIK3CAH1047R subsets.

a, Expression heat maps of selected luminal and basal genes (left: Lgr5-CreERT2/PIK3CAH1047R versus control; right: K8-CreERT2/PIK3CAH1047R versus control). LM, mature luminal cells; LP, luminal progenitors; Myo, myoepithelial; SC, stem-cell enriched. b, c, Expression profiles of basal- and luminal-lineage genes in mammary subsets of Lgr5-CreERT2/PIK3CAH1047R compared with Lgr5-CreERT2 control (b) and K8-CreERT2/PIK3CAH1047R compared with K8-CreERT2 control animals (c). The qRT–PCR results are representative of 2–3 experiments of 4 pooled animals of each genotype. Bar graphs show means ± s.e.m.; two-sided unpaired Student’s t-test; *P < 0.05; NS, not significant; N.d., not detected.

Extended Data Figure 8 Luminal PIK3CAH1047R cells repopulate a mammary gland.

a, b, Number of outgrowths in cleared-fat pad transplantation of GFP-negative Lgr5-CreERT2 control and GFP-positive Lgr5-CreERT2/PIK3CAH1047R-expressing luminal subsets (CD24HiSca1−) (a) and GFP-negative K8-CreERT2 control and GFP-positive K8-CreERT2/PIK3CAH1047R-expressing luminal subsets (left, CD24HiSca1−; right, CD24HiSca1+) (b). Representative carmine-stained whole mounts (bottom). Scale bars, 500 μm. c, Representative immunostained sections. Scale bars, 50 μm. a–c, Data from three independent experiments. d, Percentage of K14-, K8/18- and double-positive (K14/K8/18) colonies derived from Lgr5-CreERT2/PIK3CAH1047R, Lgr5-CreERT2 control (left, pooled data from n = 4 independent experiments (1–5 pooled mice)), K8-CreERT2/PIK3CAH1047R and K8-CreERT2 control subsets (right, pooled data from n = 3 independent experiments (1–5 pooled mice)). Total number of quantified colonies is shown. e, Representative images of colonies. Arrowheads indicate K8/18- (white), K14- (yellow) and double-positive (blue) colonies. Scale bars, 500 μm. f, Number of colonies derived from basal and luminal cells from Lgr5- and K8-CreERT2/PIK3CAH1047R and control mice. Left, pooled data from three independent sortings (each 1–5 pooled animals), total n = 8 (control), n = 10 (mutant) technical replicates for basal subset, n = 9 (control), n = 5 (mutant) technical replicates for luminal CD24HiSca1− subset and n = 8 (control), n = 4 (mutant) technical replicates for luminal CD24HiSca1+ subset. Right, pooled data from two independent sortings (each 1–5 pooled animals), total n = 8 (control), n = 10 (mutant) technical replicates for basal subset, n = 5 (control), n = 10 (mutant) technical replicates for luminal CD24HiSca1− subset and n = 6 (control), n = 9 (mutant) technical replicates for luminal CD24HiSca1+ subset. Five-hundred cells were seeded for each replicate. A colony was defined as a cell cluster of >5 cells. Bar graphs show means ± s.e.m.; two-sided unpaired Student’s t-test; *P < 0.05. g, Bar graphs showing number of spheres derived from FVB-control and PIK3CAH1047R-expressing luminal (CD24HiSca1−/+) mammary cells over three passages. Representative data (three replicates, n = 4 mice per genotype) from two independent experiments. Bar graphs show means ± s.d. *P < 0.02, two-sided unpaired Student’s t-test. h, Representative images of spheres derived from CD24HiSca1− cells in passage one (P1) and three (P3). Scale bars, 100 μm. N.d., not determined; NS, not significant.

Extended Data Figure 9 PIK3CAH1047R-evoked tumours express basal and luminal markers.

a, Representative FACS plots of Lgr5-CreERT2/PIK3CAH1047R and K8-CreERT2/PIK3CAH1047R tumours (n = 3). b, Percentages of total GFP-positive cells and GFP-positive basal (CD24LoSca1−) and luminal (CD24HiSca1−/+) subsets of Lgr5-CreERT2 and K8-CreERT2/PIK3CAH1047R tumours (n = 3). Bar graphs show means ± s.e.m. NS, not significant; two-sided unpaired Student’s t-test c, Immunostaining for basal and luminal markers on serial sections of a multi-nodular rosette-type adenomyoepithelioma (Lgr5-CreERT2/PIK3CAH1047R) and adenomyoepithelioma (K8-CreERT2/PIK3CAH1047R). Scale bars, 100 μm, 50 μm (magnifications). d, Quantification of basal- and luminal-lineage markers of Lgr5-CreERT2 and K8-CreERT2/PIK3CAH1047R tumours. Each dot represents one tumour (top: K8/18, K14 and SMA n = 15, K5 n = 14, ER n = 10, PR n = 9, p63 n = 8; bottom: K8/18, K14, SMA and K5 n = 15, ER, PR and p63 n = 10). All Lgr5-CreERT2/PIK3CAH1047R tumours and 8/10 and 6/10 of K8-CreERT2/PIK3CAH1047R tumours show more than 1% of ER- and/or PR-positive cells, respectively. Bar graphs show means ± s.d. e, Representative haematoxylin and eosin stainings of tumour phenotypes. Scale bars, 100 μm. f, Percentage of benign and malignant mammary tumours.

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Extended Data Figure 10 Expression profiling of K8- and Lgr5-CreERT2/PIK3CAH1047R mammary tumours.

a, Principle component analysis and dendogram of a hierarchical clustering of gene expression profiles from 10 K8- and 10 Lgr5-CreERT2/PIK3CAH1047R tumours and 2–3 reference mammary glands. Each dot indicates one sample. Circles represent K8-CreERT2 and squares represent Lgr5-CreERT2 animals expressing PIK3CAH1047R (filled symbols) or not (open symbols). b, Heat map of the top 1,000 genes that vary between K8-CreERT2/PIK3CAH1047R and Lgr5-CreERT2/PIK3CAH1047R tumours and The Cancer Genome Atlas (TCGA) human breast cancer gene signatures. Lum, luminal.

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Koren, S., Reavie, L., Couto, J. et al. PIK3CAH1047R induces multipotency and multi-lineage mammary tumours. Nature 525, 114–118 (2015). https://doi.org/10.1038/nature14669

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