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J Biol Chem. 2014 Jun 20;289(25):17620-33. doi: 10.1074/jbc.M114.570853. Epub 2014 May 6.

Histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) controls mammary gland development by regulating key developmental and lineage specification genes.

Author information

1
From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520.
2
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, and.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, and Harvard Stem Cell Institute, Cambridge, Massachusetts 02138.
4
From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, qin.yan@yale.edu.

Abstract

The JmjC domain-containing H3K4 histone demethylase jumonji AT-rich interactive domain 1B (JARID1B) (also known as KDM5B and PLU1) is overexpressed in breast cancer and is a potential target for breast cancer treatment. To investigate the in vivo function of JARID1B, we developed Jarid1b(-/-) mice and characterized their phenotypes in detail. Unlike previously reported Jarid1b(-/-) strains, the majority of these Jarid1b(-/-) mice were viable beyond embryonic and neonatal stages. This allowed us to further examine phenotypes associated with the loss of JARID1B in pubertal development and pregnancy. These Jarid1b(-/-) mice exhibited decreased body weight, premature mortality, decreased female fertility, and delayed mammary gland development. Related to these phenotypes, JARID1B loss decreased serum estrogen level and reduced mammary epithelial cell proliferation in early puberty. In mammary epithelial cells, JARID1B loss diminished the expression of key regulators for mammary morphogenesis and luminal lineage specification, including FOXA1 and estrogen receptor α. Mechanistically, JARID1B was required for GATA3 recruitment to the Foxa1 promoter to activate Foxa1 expression. These results indicate that JARID1B positively regulates mammary ductal development through both extrinsic and cell-autonomous mechanisms.

KEYWORDS:

Breast Cancer; Epigenetics; Estrogen; FOXA1; GATA3; Histone Methylation; KDM5B; Luminal Lineage; Mammary Gland Development; Mouse Genetics

PMID:
24802759
PMCID:
PMC4067197
DOI:
10.1074/jbc.M114.570853
[Indexed for MEDLINE]
Free PMC Article
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