Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner

Regan, Joseph L.; Sourisseau, Tony; Soady, Kelly; Kendrick, Howard; McCarthy, Afshan; Tang, Chan; Brennan, Keith; Linardopoulos, Spiros; White, Donald E.; Smalley, Matthew J.

doi:10.1016/j.celrep.2013.05.044

Cited by 61 publications

(59 citation statements)

References 54 publications

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“…One recent study revealed exclusively planar cell divisions within the basal, cap cell layer of the TEB, with no observed contribution of basal cells to the internal, body cell compartment (Taddei et al, 2008). Another recent study observed a minority of vertical basal cell divisions in stratified TEBs during ductal elongation (Regan et al, 2013). Both of these studies were based on the analysis of fixed sections of the mammary gland.…”

Section: Discussionmentioning

confidence: 99%

Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells

2014

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Mammary ducts are elongated during development by stratified epithelial structures, known as terminal end buds (TEBs). TEBs exhibit reduced apicobasal polarity and extensive proliferation. A major unanswered question concerns the mechanism by which the simple ductal epithelium stratifies during TEB formation. We sought to elucidate this mechanism using real-time imaging of growth factorinduced stratification in 3D cultures of mouse primary epithelial organoids. We hypothesized that stratification could result from vertical divisions in either the apically positioned luminal epithelial cells or the basally positioned myoepithelial cells. Stratification initiated exclusively from vertical apical cell divisions, both in 3D culture and in vivo. During vertical apical divisions, only the mother cell retained tight junctions and segregated apical membranes. Vertical daughter cells initiated an unpolarized cell population located between the luminal and myoepithelial cells, similar to the unpolarized body cells in the TEB. As stratification and loss of apicobasal polarity are early hallmarks of cancer, we next determined the cellular mechanism of oncogenic stratification. Expression of activated ERBB2 induced neoplastic stratification through analogous vertical divisions of apically positioned luminal epithelial cells. However, ERBB2-induced stratification was accompanied by tissue overgrowth and acute loss of both tight junctions and apical polarity. Expression of phosphomimetic MEK (MEK1DD), a major ERBB2 effector, also induced stratification through vertical apical cell divisions. However, MEK1DD-expressing organoids exhibited normal levels of growth and retained apicobasal polarity. We conclude that both normal and neoplastic stratification are accomplished through receptor tyrosine kinase signaling dependent vertical cell divisions within the luminal epithelial cell layer. KEY WORDS: Apicobasal polarity, Breast cancer, Epithelial development, Mammary gland, Mouse INTRODUCTIONSimple epithelial cells are characterized by extensive intercellular junctions and strong polarity along the apicobasal axis (Bryant and Mostov, 2008;Zegers et al., 2003). This polarity is manifested both in specialized morphological features, such as apically localized microvilli, and by segregated plasma membrane domains with distinct apical and basolateral polarity proteins (Nelson, 2003;Yeaman et al., RESEARCH ARTICLE 1999). Yet these highly polarized cells emerge during development from less polarized, multilayered embryonic tissues. Early embryonic morphogenesis in the mammary and salivary glands is accomplished by a tissue with lower levels of polarity and adhesion than the mature epithelium in the adult organ (Andrew and Ewald, 2010;Hsu and Yamada, 2010). A fundamental and unresolved question in biology is how epithelial tissues transition between these different states of organization and polarity (Nelson, 2009). These transitions are also of biomedical interest, as epithelial tumors lose apicobasal polarity and simple organi...

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Section: Discussionmentioning

confidence: 99%

Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells

2014

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“…Interestingly, Aurora-A is implicated in spindle orientation in asymmetric cell divisions in Drosophila [34] via phosphorylation of Pins [35]. Excess Aurora-A can also influence the spindle orientation and the cell fate in human mammary epithelium stem/progenitor cells [36]. In our time-lapse assays using a U2OS cell line with fluorescent MTs, we actually visualized spindle rotation movements: thus, Aurora-A activity is required for pathways that determine the mitotic spindle orientation, raising the possibility that Aurora-A inhibition influences the fate of asymmetrically dividing cells and/or tissue architecture.…”

Section: Discussionmentioning

confidence: 99%

The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy

et al. 2014

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Inhibition of Aurora kinase activity by small molecules is being actively investigated as a potential anti-cancer strategy. A successful therapeutic use of Aurora inhibitors relies on a comprehensive understanding of the effects of inactivating Aurora kinases on cell division, a challenging aim given the pleiotropic roles of those kinases during mitosis. Here we have used the Aurora-A inhibitor MLN8237, currently under phase-I/III clinical trials, in dose-response assays in U2OS human cancer cells synchronously proceeding towards mitosis. By following the behaviour and fate of single Aurora-inhibited cells in mitosis by live microscopy, we show that MLN8237 treatment affects multiple processes that are differentially sensitive to the loss of Aurora-A function. A role of Aurora-A in controlling the orientation of cell division emerges. MLN8237 treatment, even in high doses, fails to induce efficient elimination of dividing cells, or of their progeny, while inducing significant aneuploidy in daughter cells. The results of single-cell analyses show a complex cellular response to MLN8237 and evidence that its effects are strongly dose-dependent: these issues deserve consideration in the light of the design of strategies to kill cancer cells via inhibition of Aurora kinases.

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“…Moreover, analysis of partitioning of the cell fate determinant Numb showed that PKH26 hi cells in the MaSC/basal population predominantly divide through asymmetric division (Cicalese et al 2009). In addition, b1 integrin and a Notch-dependent Aurora A pathway have been implicated in regulating the cell division axis in the mammary gland (Taddei et al 2008;Regan et al 2013). The recent evaluation of mice harboring an inducible histone 2b (H2B) promoter linked to a GFP reporter (K5tTA-H2b-GFP) (Dos Santos et al 2013) revealed a small subset (0.2%) of slowly cycling H2b-GFP hi cells within the MaSC/basal population.…”

Section: Evidence For Slow-cycling and Quiescent Stem Cellsmentioning

confidence: 99%

Mammary stem cells and the differentiation hierarchy: current status and perspectives

2014

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The mammary epithelium is highly responsive to local and systemic signals, which orchestrate morphogenesis of the ductal tree during puberty and pregnancy. Based on transplantation and lineage tracing studies, a hierarchy of stem and progenitor cells has been shown to exist among the mammary epithelium. Lineage tracing has highlighted the existence of bipotent mammary stem cells (MaSCs) in situ as well as long-lived unipotent cells that drive morphogenesis and homeostasis of the ductal tree. Moreover, there is accumulating evidence for a heterogeneous MaSC compartment comprising fetal MaSCs, slow-cycling cells, and both long-term and short-term repopulating cells. In parallel, diverse luminal progenitor subtypes have been identified in mouse and human mammary tissue. Elucidation of the normal cellular hierarchy is an important step toward understanding the “cells of origin” and molecular perturbations that drive breast cancer.

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Aurora A Kinase Regulates Mammary Epithelial Cell Fate by Determining Mitotic Spindle Orientation in a Notch-Dependent Manner

Cited by 61 publications

References 54 publications

Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells

Developmental stratification of the mammary epithelium occurs through symmetry-breaking vertical divisions of apically positioned luminal cells

The Aurora-A inhibitor MLN8237 affects multiple mitotic processes and induces dose-dependent mitotic abnormalities and aneuploidy

Mammary stem cells and the differentiation hierarchy: current status and perspectives

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