Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation

Zhou, Jiong; Chehab, Renee; Tkalcevic, Josephine; Naylor, Matthew J.; Harris, Jessica; Wilson, Trevor; Tsao, Susan Elizabeth; Tellis, Irene; Zavarsek, Silva; Xu, Dakang; Lapinskas, Erika J; Visvader, Jane E.; Lindeman, Geoffrey J.; Thomas, Ross S; Ormandy, Christopher J.; Hertzog, Paul J.; Kola, Ismail; Pritchard, Melanie April

doi:10.1038/sj.emboj.7600538

Cited by 134 publications

(131 citation statements)

References 43 publications

(63 reference statements)

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“…2D). Decreased gene expression of E74-like factor 5 (ELF5), a transcription factor required for growth and differentiation of the luminal alveolar population (25)(26)(27), and the RTK gene KIT were also observed. Elf5 and c-KIT have emerged as definitive markers of the luminal progenitor population (19).…”

Section: Resultsmentioning

confidence: 99%

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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ErbB3 harbors weak kinase activity, but strongly activates downstream phosphatidylinositol 3-kinase/Akt signaling through heterodimerization with and activation by other ErbB receptor tyrosine kinases. We report here that ErbB3 loss in the luminal mammary epithelium of mice impaired Akt and MAPK signaling and reduced luminal cell proliferation and survival. ERBB3 mRNA expression levels were highest in luminal mammary populations and lowest in basal cell/stem cell populations. ErbB3 loss in mammary epithelial cells shifted gene expression patterns toward a mammary basal cell/stem cell signature. ErbB3 depletion-induced gene expression changes were rescued upon activation of Akt and MAPK signaling. Interestingly, proliferation and expansion of the mammary basal epithelium (BE) occurred upon ErbB3 targeting in the luminal epithelium, but not upon its targeting in the BE. Multiple cytokines, including interleukin 6, were induced upon ErbB3 depletion in luminal epithelium cells, which increased growth of BE cells. Taken together, these results suggest that ErbB3 regulates the balance of differentiated breast epithelial cell types by regulating their growth and survival through autocrine-and paracrinesignaling mechanisms.A berrant regulation of the ErbB family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers (1-4). This family consists of four members: HER1/ErbB1/ EGFR (epidermal growth factor receptor), HER2/ErbB2/Neu, HER3/ErbB3, and HER4/ErbB4. Except for ErbB3, which has weak kinase activity, the ErbB RTKs exhibit dimerization-induced phosphorylation and catalytic activation. In response to ligand binding, ErbBs form homodimers and heterodimers with other ErbB coreceptors. ErbB3 relies on transphosphorylation by heterodimeric partners to induce signal transduction (5-7).ErbB RTKs are required for breast development, although each receptor bears a unique spatiotemporal expression pattern. ErbB2 loss in the mammary epithelium delays ductal elongation during puberty and disorganizes cells within terminal end buds (TEBs) (8-10). EGFR and ErbB4 are not required for mammary ductal development. Rather, EGFR is expressed in the basal epithelium (BE) and in the mammary stroma, and ErbB4 is necessary for milk production (11,12). Although classical knockout of mouse ErbB3 results in embryonic lethality (13), transplant experiments showed that ErbB3 drives growth of the mammary epithelium during puberty (8). Although the mechanism(s) by which ErbB2 and ErbB3 regulate growth of the ductal epithelium are currently unknown, such knowledge will impact our understanding of the earliest events contributing to the formation of ErbB2/HER2-amplified breast cancers, which account for 20-30% of all breast cancers. ErbB3-ErbB2 heterodimers are the most potent oncogenic ErbB-signaling pair due in part to strong ErbB3-induced phosphatidylinositol 3-kinase (PI3K) activation in response to ErbB3 tyrosine phosphorylation at six PI3K interaction motifs (14,15).To understand the role of ErbB3 in mammary gland dev...

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Section: Resultsmentioning

confidence: 99%

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Balko¹,

Miller

Morrison³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Among genes overexpressed in NTG cells were genes implicated in luminal breast cell function, such as whey acidic protein (Wap) and lactotransferrin (Ltf), as well as the luminal breast epithelial marker Elf5 [36] and claudin 1 (Cldn1) [37]. Elf5 is an epithelial-specific ETS transcription factor that is required for proliferation and differentiation of mouse mammary alveolar epithelial cells during pregnancy and lactation [38]. These data concur with our observations of differential cytokeratin expression and indicate that the NTG population includes cells that display a more mature epithelial cell phenotype than TG cells.…”

Section: Microarray Analysis Of the Mmtv-wnt-1 Tumorigenic Cellsmentioning

confidence: 99%

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors

et al. 2007

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Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells. STEM CELLS 2008;26:364 -371 Disclosure of potential conflicts of interest is found at the end of this article.

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“…Knocking out Elf5, the murine homologue of the human ESE-2 gene, results in embryonic lethality, which indicates that Elf5 is essential for embryonic development. Heterozygous Elf5 mice show complete developmental arrest of the mammary gland in pregnant mice [22].…”

Section: Introductionmentioning

confidence: 99%

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

Duan

Cao

et al. 2008

Cell Res

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Airway inflammation is the hallmark of many respiratory disorders, such as asthma and cystic fibrosis. Changes in airway gene expression triggered by inflammation play a key role in the pathogenesis of these diseases. Genetic linkage studies suggest that ESE-2 and ESE-3, which encode epithelium-specific Ets-domain-containing transcription factors, are candidate asthma susceptibility genes. We report here that the expression of another member of the Ets family transcription factors ESE-1, as well as ESE-3, is upregulated by the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in bronchial epithelial cell lines. Treatment of these cells with IL-1β and TNF-α resulted in a dramatic increase in mRNA expression for both ESE-1 and ESE-3. We demonstrate that the induced expression is mediated by activation of the transcription factor NF-κB. We have characterized the ESE-1 and ESE-3 promoters and have identified the NF-κB binding sequences that are required for the cytokine-induced expression. In addition, we also demonstrate that ESE-1 upregulates ESE-3 expression and downregulates its own induction by cytokines. Finally, we have shown that in Elf3 (homologous to human ESE-1) knockout mice, the expression of the inflammatory cytokine interleukin-6 (IL-6) is downregulated. Our findings suggest that ESE-1 and ESE-3 play an important role in airway inflammation.

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Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation

Cited by 134 publications

References 43 publications

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium

Isolation and Molecular Characterization of Cancer Stem Cells in MMTV-Wnt-1 Murine Breast Tumors

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

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