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J Mammary Gland Biol Neoplasia. 2019 Jun 19. doi: 10.1007/s10911-019-09432-4. [Epub ahead of print]

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

Author information

1
Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
2
Division of Molecular Carcinogenisis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.
3
Mouse Clinic for Cancer and Aging - Transgenic facility, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands.
4
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
5
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. w.zwart@nki.nl.
6
Laboratory of Chemical Biology and Institute for Complex Molecular systems, Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, Eindhoven, The Netherlands. w.zwart@nki.nl.
7
Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. j.jonkers@nki.nl.

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:

Breast cancer; Cistromic re-programming; GATA3; Truncating mutations

PMID:
31218575
DOI:
10.1007/s10911-019-09432-4

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