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PMID:25655704

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Citation

Lindley, LE, Curtis, KM, Sanchez-Mejias, A, Rieger, ME, Robbins, DJ and Briegel, KJ (2015) The WNT-controlled transcriptional regulator LBH is required for mammary stem cell expansion and maintenance of the basal lineage. Development 142:893-904

Abstract

The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis.

Links

PubMed PMC4352974 Online version:10.1242/dev.110403

Keywords

Animals; Cell Differentiation/physiology; Cell Lineage; Female; Flow Cytometry; Immunohistochemistry; Mammary Glands, Animal/metabolism; Mice; Mice, Knockout; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Pregnancy; Real-Time Polymerase Chain Reaction; Stem Cells/cytology; Stem Cells/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:LBH

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ESR1

involved_in

GO:0048863: stem cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:0060644: mammary gland epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:0010468: regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:1904674: positive regulation of somatic stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:2000737: negative regulation of stem cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:1904677: positive regulation of somatic stem cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:2000103: positive regulation of mammary stem cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

involved_in

GO:0030879: mammary gland development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LBH

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:P63

involved_in

GO:0033147: negative regulation of intracellular estrogen receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:P63

involved_in

GO:1904674: positive regulation of somatic stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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