Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

Siegel, Peter M.; Muller, William J.

doi:10.1038/onc.2010.43

Cited by 41 publications

(34 citation statements)

References 57 publications

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“…The increase in STAT5A activation (as shown by nuclear immunostaining in Fig. 3), which is mainly lactation dependent (Liu et al 1997, Siegel & Muller 2010, also agrees with the increases in milk protein levels. Finally, at PND50, we found a significant increase in Elf5 expression with V and GV treatment (Table 3) in 80-90% animals (not shown).…”

Section: Discussionsupporting

confidence: 63%

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

Saad

Toullec

Vacher

et al. 2012

Journal of Endocrinology

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Exposure to low doses of environmental estrogens such as bisphenol A and genistein (G) alters mammary gland development. The effects of environmental anti-androgens, such as the fungicide vinclozolin (V), on mammary gland morphogenesis are unknown. We previously reported that perinatal exposure to G, V, and the GV combination causes histological changes in the mammary gland during the peripubertal period, suggesting alterations to the peripubertal hormone response. We now investigate whether perinatal exposure to these compounds alters the gene expression profiles of the developing glands to identify the dysregulated signaling pathways and the underlying mechanisms. G, V, or GV (1 mg/kg body weight per day) was added to diet of Wistar rats, from conception to weaning; female offspring mammary glands were collected at postnatal days (PNDs) 35 and 50. Genes displaying differential expression and belonging to different functional categories were validated by quantitative PCR and immunocytochemistry. At PND35, G had little effect; the slight changes noted were in genes related to morphogenesis. The changes following exposure to V concerned the functional categories associated with development (Cldn1, Krt17, and Sprr1a), carbohydrate metabolism, and steroidogenesis. The GV mixture upregulated genes (Krt17, Pvalb, and Tnni2) involved in muscle development, indicating effects on myoepithelial cells during mammary gland morphogenesis. Importantly, at PND50, cycling females exposed to GV showed an increase in the expression of genes (Csn2, Wap, and Elf5) related to differentiation, consistent with the previously reported abnormal lobuloalveolar development previously described. Thus, perinatal exposure to GV alters the mammary gland hormone response differently at PND35 (puberty) and in animals with established cycles.

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Section: Discussionsupporting

confidence: 63%

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

Saad

Toullec

Vacher

et al. 2012

Journal of Endocrinology

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“…A better understanding of these mechanisms is important given the similarities of normal and cancer stem cell hierarchies and gene expression (Beck and Blanpain, 2013;Nguyen et al, 2012), as well as the prognostic significance of MaSC transcriptional signatures in breast cancer patients (Pece et al, 2010;Siegel and Muller, 2010;Soady et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance

Mohapatra

Zutshi

et al. 2017

Development

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The ubiquitin ligases CBL and CBL-B are negative regulators of tyrosine kinase signaling with established roles in the immune system. However, their physiological roles in epithelial tissues are unknown. Here, we used MMTV-Cre-mediated Cbl gene deletion on a Cbl-b null background, as well as a tamoxifen-inducible mammary stem cell (MaSC)-specific Cbl and Cbl-b double knockout (Cbl/Cbl-b DKO) using Lgr5-EGFP-IRES-CreERT2, to demonstrate a mammary epithelial cell-autonomous requirement of CBL and CBL-B in the maintenance of MaSCs. Using a newly engineered tamoxifeninducible Cbl and Cbl-b deletion model with a dual fluorescent reporter (Cbl flox/flox ; Cbl-b flox/flox ; Rosa26-CreERT; mT/mG), we show that Cbl/Cbl-b DKO in mammary organoids leads to hyperactivation of AKT-mTOR signaling with depletion of MaSCs. Chemical inhibition of AKT or mTOR rescued MaSCs from Cbl/Cbl-b DKO-induced depletion. Our studies reveal a novel, cell-autonomous requirement of CBL and CBL-B in epithelial stem cell maintenance during organ development and remodeling through modulation of mTOR signaling.

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“…The ducts are comprised of a luminal epithelial layer overlaid by a basal layer, which consists mainly of myoepithelial cells. A multipotent mammary stem cell acts as a common progenitor for the luminal and myoepithelial lineages (Siegel and Muller 2010). Notch signaling acts to commit progenitors to the luminal lineage (Bouras et al 2008;Raouf et al 2008;Yalcin-Ozuysal et al 2010), but very little is known about the mechanisms regulating the formation of myoepithelial cells.…”

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confidence: 99%

Sustained activation of the HER1–ERK1/2–RSK signaling pathway controls myoepithelial cell fate in human mammary tissue

Pašić¹,

Eisinger-Mathason²,

Velayudhan³

et al. 2011

Genes Dev.

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Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model.

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Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

Cited by 41 publications

References 57 publications

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

In utero and lactational exposure to vinclozolin and genistein induces genomic changes in the rat mammary gland

An essential role of CBL and CBL-B ubiquitin ligases in mammary stem cell maintenance

Sustained activation of the HER1–ERK1/2–RSK signaling pathway controls myoepithelial cell fate in human mammary tissue

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