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Journal of Mammary Gland Biology and Neoplasia

, Volume 24, Issue 3, pp 271–284 | Cite as

GATA3 Truncating Mutations Promote Cistromic Re-Programming In Vitro, but Not Mammary Tumor Formation in Mice

  • Lisette M. Cornelissen
  • Roebi de Bruijn
  • Linda Henneman
  • Yongsoo Kim
  • Wilbert ZwartEmail author
  • Jos JonkersEmail author
Article

Abstract

Heterozygous mutations in the transcription factor GATA3 are identified in 10–15% of all breast cancer cases. Most of these are protein-truncating mutations, concentrated within or downstream of the second GATA-type zinc-finger domain. Here, we investigated the functional consequences of expression of two truncated GATA3 mutants, in vitro in breast cancer cell lines and in vivo in the mouse mammary gland. We found that the truncated GATA3 mutants display altered DNA binding activity caused by preferred tethering through FOXA1. In addition, expression of the truncated GATA3 mutants reduces E-cadherin expression and promotes anchorage-independent growth in vitro. However, we could not identify any effects of truncated GATA3 expression on mammary gland development or mammary tumor formation in mice. Together, our results demonstrate that both truncated GATA3 mutants promote cistromic re-programming of GATA3 in vitro, but these mutants are not sufficient to induce tumor formation in mice.

Keywords

GATA3 Breast cancer Truncating mutations Cistromic re-programming 

Notes

Acknowledgements

We are grateful to Anne Paulien Drenth, Eline van der Burg and Eva Schut for their technical support with the animal studies. We thank the Netherlands Cancer Institute Genomics Core Facility, Mouse Clinic for Cancer and Aging, Animal Facility, and Animal Pathology Facility for their expert technical support.

GEO accession number

GSE122849.

Statement of Author Contributions

LMC, WZ and JJ designed research. LMC and LH performed research. LMC, RB, YK, WZ and JJ analyzed data. LMC, WZ and JJ wrote the paper.

Funding Sources

This work was financially supported by the Oncode Institute; the Center for Translational Molecular Medicine (CTMM) Breast Care Project; the Netherlands Organization for Scientific Research (NWO: Cancer Genomics Netherlands (CGCNL), Cancer Systems Biology Center (CSBC), Zenith 93512009, Vici 91814643); the EU Seventh Framework Program (EurocanPlatform project 260791); the European Research Council (ERC Synergy project CombatCancer); and a National Roadmap grant for Large-Scale Research facilities from NWO.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that there are no conflicts of interest

Supplementary material

10911_2019_9432_Fig6_ESM.png (136 kb)
Supplementary Fig. S1

Cistromic re-programming of truncated GATA3 in breast cancer cell lines. (A) Heatmap indicating raw peak intensity of total GATA3 ChIP-seq in T47D (GATA3 WT) and MCF7 (GATA3D336fs) cells, separated in shared, WT GATA3-specific and truncated GATA3-specific sites. A window of 5 kb around the peak is shown. (B,C) Average read count profiles of the total GATA3 peak signal at shared, WT GATA3-specific and truncated GATA3-specific sites for T47D (B) and MCF7 (C) cells. Average read counts at the center of the peaks were compared, ANOVA: *** p < 0.001, ns p > 0.05. A.U., arbitrary units. (D,E) Average read count profiles of the peak signal at shared (D) and WT (E) GATA3-specific sites, comparing siNT versus siFOXA1 conditions. Average read counts at the center of the peaks were compared, ANOVA: * p < 0.05, ** p < 0.01, *** p < 0.001. (PNG 135 kb)

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Supplementary Fig. S2

Truncated GATA3 expression in T47D cells does not affect cell proliferation, migration and anchorage-independent growth. (A) Cell proliferation of T47D cells expressing either WT or truncated GATA3 remained similar, as quantified using IncuCyte imaging for 250 h. Data represent mean ± standard error of the mean (SEM). (B) T47D cells expressing either WT or truncated GATA3 were scratch-wounded with a micropipette tip. The scratch area was determined by taking images at day 0, 2, 6 and 10 (black dotted lines represent the borders of the scratch). (C) The relative scratch area, calculated as the ratio between the given time point and day 0, is shown for one representative experiment. Data represent mean + SD, n = 4. No significant differences (two-way ANOVA). (D) Representative images of soft agar colony formation at day 14 after plating of T47D cells expressing WT or truncated GATA3. (E) Quantification of a representative experiment at day 7 and 14 after plating, as measured using the GelCount software. Data represent mean + standard deviation (SD), n = 2. No significant differences (ANOVA). (PNG 259 kb)

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High Resolution Image (TIF 7366 kb)
10911_2019_9432_Fig8_ESM.png (115 kb)
Supplementary Fig. S3

Differential binding of truncated GATA3 does not result in distinct gene expression changes. (A) Unsupervised hierarchical clustering analysis using the top 1000 most variable expressed genes of 2 biological replicates of the T47D Empty vector, HA-hGATA3WT, HA-hGATA3TR1 and HA-hGATA3TR2 cell lines. (B) Principal component analysis (PCA) plot based on RNA-sequencing, showing the separation of the different GATA3 mutant cell lines. (C) Volcano plots indicating the differentially expressed genes of HA-hGATA3WT (left), HA-hGATA3TR1 (middle) and HA-hGATA3TR2 (right) expressing cell lines compared to empty vector. FDR, false discovery rate. Log2FC, Log2 fold change. (D-F) Expression levels of genes associated with shared binding events (D), WT GATA3-specific binding events (E) and truncated GATA3-specific binding events (F) for all cell lines. (PNG 114 kb)

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High Resolution Image (TIF 2306 kb)
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Supplementary Fig. S4

Truncated GATA3 expression does not affect mouse mammary gland development. (A,B) Representative images of carmine-stained mammary glands of MMTV-cre;mT/mG;mGATA3WT (mGATA3WT) and MMTV-cre;mT/mG;mGATA3TR2 (mGATA3TR2) mice at three weeks (A) and nine weeks (B) of age are shown (left; scale bars, 2.5 mm). Representative microscopic images of H&E staining and for GFP expression by immunohistochemistry are shown below (right; scale bars, 200 μm). (C,D) Quantification of ductal invasion at three (mGATA3WTn = 3; mGATA3TR2 n = 3), six (mGATA3WTn = 5; mGATA3TR1 n = 3; mGATA3TR2n = 4) and ten (mGATA3WT n = 3; mGATA3TR2 n = 3) weeks of age, determined in one inguinal gland per mouse. Ductal invasion was determined as the absolute length of the mammary fat pad invaded by the ductal structure (C) and as the length of the ductal structure as a percentage of the total length of the mammary fat pad (D), as measured using ImageJ. Data represent mean + SD, no significant differences (three and ten weeks, T-test; six weeks, ANOVA). (E,F) Quantification of ductal invasion in mGATA3WT and mGATA3 TR2, as shown in (C,D), reflecting the ductal invasion over time. Data represent mean ± SD. (PNG 446 kb)

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Supplementary Fig. S5

Truncated GATA3 expression does not induce mammary tumor formation in mice. (A,B) Representative microscopic images of H&E staining of aged glands from both Wap-Cre;mGATA3TR1 and Wap-Cre;mGATA3TR2 mice. In both models healthy (A) and dilated (B) ducts were identified. Scale bars, 300 μm. (C) Kaplan-Meier analysis of overall survival of Wap-Cre;mGATA3TR1 (n = 19) and Wap-Cre;mGATA3TR2 (n = 10) mice. Wap-Cre;mGATA3TR2 mice show reduced survival compared to Wap-Cre;mGATA3TR1 mice. Mantel-cox: 427 days versus >565 days, *** p < 0.001. (D) A comparison between Wap-Cre;mGATA3TR1 and Wap-Cre;mGATA3TR2 of the amount of animals sacrificed due to illness versus the amount of animals reaching the endpoint of the experiment. Fisher’s exact: ns p > 0.05. (PNG 152 kb)

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10911_2019_9432_MOESM6_ESM.docx (16 kb)
Supplementary Table S1 (DOCX 16 kb)
10911_2019_9432_MOESM7_ESM.docx (15 kb)
Supplementary Table S2 (DOCX 15 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Molecular Pathology, Oncode InstituteThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Division of Molecular Carcinogenisis, Oncode InstituteThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Mouse Clinic for Cancer and Aging – Transgenic facilityThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Division of Oncogenomics, Oncode InstituteThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  5. 5.Laboratory of Chemical Biology and Institute for Complex Molecular systems, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenThe Netherlands

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