GATA-3 Maintains the Differentiation of the Luminal Cell Fate in the Mammary Gland

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2006 Nov 30

PMID 17129787

Citations 344

Authors

Hosein Kouros-Mehr

Euan M Slorach

Mark D Sternlicht

Zena Werb

Affiliations

Soon will be listed here.

Abstract

The GATA family of transcription factors plays fundamental roles in cell-fate specification. However, it is unclear if these genes are necessary for the maintenance of cellular differentiation after development. We identified GATA-3 as the most highly enriched transcription factor in the mammary epithelium of pubertal mice. GATA-3 was found in the luminal cells of mammary ducts and the body cells of terminal end buds (TEBs). Upon conditional deletion of GATA-3, mice exhibited severe defects in mammary development due to failure in TEB formation during puberty. After acute GATA-3 loss, adult mice exhibited undifferentiated luminal cell expansion with basement-membrane detachment, which led to caspase-mediated cell death in the long term. Further, FOXA1 was identified as a downstream target of GATA-3 in the mammary gland. This suggests that GATA-3 actively maintains luminal epithelial differentiation in the adult mammary gland, which raises important implications for the pathogenesis of breast cancer.

Citing Articles

Roles of Post-Translational Modifications of Transcription Factors Involved in Breast Cancer Hypoxia.

Seymour L, Nuru N, Johnson K, Gutierrez J, Njoku V, Darie C Molecules. 2025; 30(3).

PMID: 39942749 PMC: 11820228. DOI: 10.3390/molecules30030645.

Classification of Breast Cancer Through the Perspective of Cell Identity Models.

Iggo R, MacGrogan G Adv Exp Med Biol. 2025; 1464():185-207.

PMID: 39821027 DOI: 10.1007/978-3-031-70875-6_11.

Mechanisms of Regulation of Cell Fate in Breast Development and Cancer.

Van Keymeulen A Adv Exp Med Biol. 2025; 1464():167-184.

PMID: 39821026 DOI: 10.1007/978-3-031-70875-6_10.

Unveiling GATA3 Signaling Pathways in Health and Disease: Mechanisms, Implications, and Therapeutic Potential.

Bacha R, Alwisi N, Ismail R, Pedersen S, Al-Mansoori L Cells. 2025; 13(24.

PMID: 39768217 PMC: 11674286. DOI: 10.3390/cells13242127.

Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility.

Sayaman R, Miyano M, Carlson E, Senapati P, Zirbes A, Shalabi S Elife. 2024; 13.

PMID: 39545637 PMC: 11723586. DOI: 10.7554/eLife.95720.

References

Utomo A, Nikitin A, Lee W . Temporal, spatial, and cell type-specific control of Cre-mediated DNA recombination in transgenic mice. Nat Biotechnol. 1999; 17(11):1091-6. DOI: 10.1038/15073. View

Sternlicht M, Kouros-Mehr H, Lu P, Werb Z . Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006; 74(7):365-81. PMC: 2580831. DOI: 10.1111/j.1432-0436.2006.00105.x. View

Bertucci F, Houlgatte R, Benziane A, Granjeaud S, Adelaide J, Tagett R . Gene expression profiling of primary breast carcinomas using arrays of candidate genes. Hum Mol Genet. 2000; 9(20):2981-91. DOI: 10.1093/hmg/9.20.2981. View

Gruvberger S, Ringner M, Chen Y, Panavally S, Saal L, Borg A . Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 2001; 61(16):5979-84. View

Cantor A, Orkin S . Hematopoietic development: a balancing act. Curr Opin Genet Dev. 2001; 11(5):513-9. DOI: 10.1016/s0959-437x(00)00226-4. View

Frisch S, Screaton R . Anoikis mechanisms. Curr Opin Cell Biol. 2001; 13(5):555-62. DOI: 10.1016/s0955-0674(00)00251-9. View

West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R . Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S A. 2001; 98(20):11462-7. PMC: 58752. DOI: 10.1073/pnas.201162998. View

Jacobsen C, Narita N, Bielinska M, Syder A, Gordon J, Wilson D . Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium. Dev Biol. 2002; 241(1):34-46. DOI: 10.1006/dbio.2001.0424. View

Wagner K, McAllister K, Ward T, Davis B, Wiseman R, Hennighausen L . Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res. 2002; 10(6):545-53. DOI: 10.1023/a:1013063514007. View

10.

J van t Veer L, Dai H, van de Vijver M, He Y, Hart A, Mao M . Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002; 415(6871):530-6. DOI: 10.1038/415530a. View

11.

Davidson E, Rast J, Oliveri P, Ransick A, Calestani C, Yuh C . A genomic regulatory network for development. Science. 2002; 295(5560):1669-78. DOI: 10.1126/science.1069883. View

12.

Yang H, Lu M, Zhang L, Whitsett J, Morrisey E . GATA6 regulates differentiation of distal lung epithelium. Development. 2002; 129(9):2233-46. DOI: 10.1242/dev.129.9.2233. View

13.

Welm B, Tepera S, Venezia T, Graubert T, Rosen J, Goodell M . Sca-1(pos) cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol. 2002; 245(1):42-56. DOI: 10.1006/dbio.2002.0625. View

14.

Grogan J, Locksley R . T helper cell differentiation: on again, off again. Curr Opin Immunol. 2002; 14(3):366-72. DOI: 10.1016/s0952-7915(02)00340-0. View

15.

Wiseman B, Werb Z . Stromal effects on mammary gland development and breast cancer. Science. 2002; 296(5570):1046-9. PMC: 2788989. DOI: 10.1126/science.1067431. View

16.

Patient R, McGhee J . The GATA family (vertebrates and invertebrates). Curr Opin Genet Dev. 2002; 12(4):416-22. DOI: 10.1016/s0959-437x(02)00319-2. View

17.

Kuo W, Stokke T, Hovig E . Associations between gene expressions in breast cancer and patient survival. Hum Genet. 2002; 111(4-5):411-20. DOI: 10.1007/s00439-002-0804-5. View

18.

Barczak A, Rodriguez M, Hanspers K, Koth L, Tai Y, Bolstad B . Spotted long oligonucleotide arrays for human gene expression analysis. Genome Res. 2003; 13(7):1775-85. PMC: 403751. DOI: 10.1101/gr.1048803. View

19.

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron J, Nobel A . Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003; 100(14):8418-23. PMC: 166244. DOI: 10.1073/pnas.0932692100. View

20.

Sotiriou C, Neo S, McShane L, Korn E, Long P, Jazaeri A . Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003; 100(18):10393-8. PMC: 193572. DOI: 10.1073/pnas.1732912100. View