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Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation

Nature Cell Biology volume 9, pages 201–209 (2007)Cite this article

Abstract

The transcription factor Gata-3 is a defining marker of the 'luminal' subtypes of breast cancer1,2,3,4. To gain insight into the role of Gata-3 in breast epithelial development and oncogenesis, we have explored its normal function within the mammary gland by conditionally deleting Gata-3 at different stages of development. We report that Gata-3 has essential roles in the morphogenesis of the mammary gland in both the embryo and adult. Through the discovery of a novel marker (β3-integrin) of luminal progenitor cells and their purification, we demonstrate that Gata-3 deficiency leads to an expansion of luminal progenitors and a concomitant block in differentiation. Remarkably, introduction of Gata-3 into a stem cell-enriched population induced maturation along the alveolar luminal lineage. These studies provide evidence for the existence of an epithelial hierarchy within the mammary gland and establish Gata-3 as a critical regulator of luminal differentiation.

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Figure 1: Gata-3 deficiency results in loss of mammary glands.
Figure 2: Impaired development in MMTV–cre;Gata-3f/f mammary glands.
Figure 3: Impaired development in WAP–cre;Gata-3f/f mammary glands.
Figure 4: CD61 (β3-integrin) is a marker of luminal progenitor cells in the mammary gland.
Figure 5: Expansion of CD61+ progenitor cells in Gata-3-deficient mammary glands and role of Gata-3 in lineage-determination.

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Acknowledgements

We are grateful to S. Holroyd and K. Johnson for expert technical assistance, F. Vaillant, J. Adams and K. Lim for discussions, S. Mihajlovic for histology, F. Battye and K. Field for FACS support, K.-U. Wagner and L. Hennighausen for WAP–cre and MMTV–cre transgenic mice, J. Jonkers for K14–cre mice, and H. Clevers for Lef1 plasmid. G.J.L. and J.E.V. are Research Fellows of the National Health and Medical Research Council (NHMRC) of Australia. M.-L.A.-L. is supported by an INSERM/NHMRC Postdoctoral Fellowship. M.S. was supported by a NHMRC Medical Postgraduate Scholarship. This work was supported by the Victorian Breast Cancer Research Consortium (J.E.V and G.J.L).

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Author notes

  1. Kate D. Sutherland

    Present address: The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

  2. Mark Shackleton

    Present address: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, 48109, USA

  3. Marie-Liesse Asselin-Labat and Kate D. Sutherland: These authors contributed equally to this work.

Authors and Affiliations

  1. VBCRC Laboratory, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Marie-Liesse Asselin-Labat, Kate D. Sutherland, Holly Barker, Richard Thomas, Mark Shackleton, Natasha C. Forrest, Geoffrey J. Lindeman & Jane E. Visvader

  2. Department of Medical Biology, The University of Melbourne, Parkville, 3010, Victoria, Australia

    Holly Barker & Mark Shackleton

  3. Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3050, Victoria, Australia

    Lynne Hartley & Lorraine Robb

  4. Department of Cell Biology, Erasmus Medical Center, 3000 DR, Rotterdam, The Netherlands

    Frank G. Grosveld & Jacqueline van der Wees

  5. Department of Medical Oncology, Royal Melbourne Hospital, Parkville, 3050, Victoria, Australia

    Geoffrey J. Lindeman

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Correspondence to Geoffrey J. Lindeman or Jane E. Visvader.

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Asselin-Labat, ML., Sutherland, K., Barker, H. et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol 9, 201–209 (2007). https://doi.org/10.1038/ncb1530

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