<i>Numb</i>
            and
            <i>Numbl</i>
            act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis

Zhang, Yue; Li, Fengyin; Song, Yongli; Sheng, Xiaole; Ren, Fazheng; Xiong, Kai; Chen, Lei; Zhang, Hongquan; Liu, Dequan; Lengner, Christopher J.; Xue, Lixiang; Yu, Zhengquan

doi:10.1096/fj.201600387r

Cited by 29 publications

(40 citation statements)

References 43 publications

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“…In addition, in the current study, though it was difficult to count the secondary and tertiary ductal branches of mammary glands during late pregnancy and lactation, we observed an obvious decrease in alveolar buds and enlarged alveolar lumina after mifepristone treatment. Furthermore, an enlarged alveolar lumen after mifepristone administration is in accordance with a previous report, showing that that loss of mammary gland development associated gene Numb or Numbl/l, leading to an enlarged lumen of alveoli and failure in lactation during pregnancy in mice (Zhang et al, 2016). Mifepristone decreased P 4 or E 2 levels on Pd7, these results were in agreement with previous reports, in which P 4 or E 2 levels declined two days after mifepristone administration in humans or mice (Somell et al, 1990;Chen et al, 2015).…”

Section: Discussionsupporting

confidence: 92%

Mifepristone Treatment in Pregnant Murine Model Induced Mammary Gland Dysplasia and Postpartum Hypogalactia

Zhu

Jia

Ren

et al. 2020

Front. Cell Dev. Biol.

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Mammary gland dysplasia and postpartum hypogalactia often occur in humans and in the livestock breeding industry. However, their underlying mechanisms are not clear yet. Mifepristone, which has a high affinity for progesterone (P 4 ) and glucocorticoid receptors, was exploited here to induce the disorders of mammary gland development and lactation. Four strategies were devised for treating pregnant mice with mifepristone. In the first strategy, mice were administered 1.20 mg mifepristone/kg body weight (BW) on pregnancy day 4 (Pd4). In the second strategy, mifepristone was administered to mice twice, with 1.20 mg/kg BW on Pd4 and 0.40 mg/kg BW on Pd8. In the third strategy, mice were treated with a single dose of 0.40 mg mifepristone/kg BW on Pd8. In the fourth strategy, mice were administered 0.40 mg mifepristone/kg BW on Pd8 and 0.20 mg mifepristone/kg BW on Pd12. The results suggested that mifepristone administration at the dose of 1.20 mg/kg BW on Pd4 caused significant reduction in milk production on lactation day 1 (Ld1), Ld2, and Ld3, as assessed using a weighsuckle-weigh assay. Mammary β-casein expression, milk yields, litter growth rates, gland structure, and serum concentrations of 17-β estrogen (E 2 ), P 4 , prolactin (PRL), growth hormone (GH), corticosterone (CORT) and oxytocin (OT) as well as the receptors of these hormones were determined during pregnancy or lactation after performing the first (Pd4) strategy. The results demonstrated that mifepristone administration during early pregnancy decreased β-casein expression, milk yields and litter growth rates, induced fewer alveoli, enlarged alveolar lumina, and altered the levels of E 2 , P 4 , PRL, GH, CORT, and OT as well as the mRNA expression of these hormonal receptors during pregnancy or early lactation. The present study on pregnant mice treated with mifepristone offers an innovative murine model to study the mechanism underlying mammary gland dysplasia and postpartum hypogalactia.

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Section: Discussionsupporting

confidence: 92%

Mifepristone Treatment in Pregnant Murine Model Induced Mammary Gland Dysplasia and Postpartum Hypogalactia

Zhu

Jia

Ren

et al. 2020

Front. Cell Dev. Biol.

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“…1C). These observations mimic earlier observations made in multiple contexts such as mammary gland development 16 , MCF10A cells 17 , MDCK cells 18 , and esophageal cancer cells 19 . Further, knockdown of Numb or Numbl lead to inhibition of cell proliferation, a trait also typically associated with EMT progression 20 (Fig.…”

Section: Numb Knockdown Drives Hybrid E/m Cells To a Completely Mesensupporting

confidence: 89%

Numb prevents a complete EMT by modulating Notch signalling

Bocci

Jolly

Tripathi

et al. 2017

Preprint

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Epithelial-Mesenchymal Transition (EMT) plays key roles during embryonic development, wound healing, and cancer metastasis. Cells in a partial EMT or hybrid epithelial/mesenchymal (E/M) phenotype tend to exhibit collective cell migration, forming clusters of circulating tumour cells -the primary drivers of metastasis. Activation of cell-cell signalling pathways such as Notch fosters a partial or complete EMT, yet the mechanisms enabling cluster formation remain poorly understood. Using an integrated computational-experimental approach, we examine the role of Numban inhibitor of Notch intercellular signallingin mediating EMT and clusters formation of hybrid E/M cells. Knockdown of Numb in stable hybrid E/M cells H1975 results in a full EMT, thereby showing that Numb acts as a brake for a full EMT. Consistent with this observation, weshow via a mathematical model that Numb inhibits a full EMT by stabilizing a hybrid E/M phenotype. Thus, Numb can behave as a 'phenotypic stability factor' by modulating Notchdriven EMT. By generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumour-initiation ability. Finally, Numb correlates with a poor survival in multiple 3 independent lung and ovarian cancer datasets, hence confirming its relationship with increased cancer aggressiveness.Major Findings: we adopt an integrative computational-experimental approach to identify that Numb, an inhibitor of Notch signalling, can stabilize a hybrid epithelial/mesenchymal (E/M) phenotype. We show that knockdown of Numb in H1975 cells that display a stable hybrid E/M state is sufficient to destabilize a hybrid E/M state and push them to a full EMT phenotype. Next, we develop a mechanism-based mathematical model that recapitulates this ability of Numb in maintaining a hybrid E/M state, and predicts that Numb can alter the relative frequency of hybrid E/M and mesenchymal cells at a tissue level or in clusters of circulating tumor cells (CTCs)the primary drivers of metastasis. Finally, we show that across cancer types, Numb correlates with worse patient survival, thus reinforcing the emerging notion that a hybrid E/M, but not necessarily a completely mesenchymal, phenotype associates with elevated tumour progression.

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“…Therefore, in addition to 'conventional' PSF proteins that promote a partial EMT through direct crosstalk with the EMT regulatory circuitry, such as OVOL, GRHL2, and NRF2 [51,52,62], other PSFs can facilitate a partial EMT and the formation of CTC clusters by activating Notch-Jagged signaling and/or inhibiting Notch-Delta signaling. For example, NUMB/NUMBL that forms a negative feedback loop with Notch [92][93][94] can prevent a complete EMT, and consistent with that identification, knockdown of NUMB/ NUMBL result in a mesenchymal phenotype and enables individual migration of the hybrid E/M NSCLC H1975 cells that typically migrate collectively [53]. expression, which supports the role of ZEB1 in mediating EMT [42,44].…”

Section: In Vivo Characterization Of Hybrid E/m Phenotypessupporting

confidence: 73%

Quantifying Cancer Epithelial-Mesenchymal Plasticity and Its Association with Stemness and Immune Response

Jia

Bocci

et al. 2019

Preprint

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Cancer cells can acquire a spectrum of stable hybrid epithelial/mesenchymal (E/M) states during epithelial-mesenchymal transition (EMT). Cells in these hybrid E/M phenotypes often combine epithelial and mesenchymal features and tend to migrate collectively commonly as small clusters. Such collectively migrating cancer cells play a pivotal role in seeding metastases and their presence in cancer patients indicates an adverse prognostic factor. Moreover, cancer cells in hybrid E/M phenotypes tend to be more associated with stemness which endows them with tumor-initiation ability and therapy resistance. Most recently, cells undergoing EMT have been shown to promote immune suppression for better survival. A systematic understanding of the emergence of hybrid E/M phenotypes and the connection of EMT with stemness and immune suppression would contribute to more effective therapeutic strategies. In this review, we first discuss recent efforts combining theoretical and experimental approaches to elucidate mechanisms underlying EMT multi-stability (i.e. the existence of multiple stable phenotypes during EMT) and the properties of hybrid E/M phenotypes. Following we discuss non-cell-autonomous regulation of EMT by cell cooperation and extracellular matrix. Afterwards, we discuss various metrics that can be used to quantify EMT spectrum. We further describe possible mechanisms underlying the formation of clusters of circulating tumor cells. Last but not least, we summarize recent systems biology analysis of the role of EMT in the acquisition of stemness and immune suppression.

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Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis

Cited by 29 publications

References 43 publications

Mifepristone Treatment in Pregnant Murine Model Induced Mammary Gland Dysplasia and Postpartum Hypogalactia

Mifepristone Treatment in Pregnant Murine Model Induced Mammary Gland Dysplasia and Postpartum Hypogalactia

Numb prevents a complete EMT by modulating Notch signalling

Quantifying Cancer Epithelial-Mesenchymal Plasticity and Its Association with Stemness and Immune Response

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