Plasticity of Mammary Cell Boundaries Governed by EGF and Actin Remodeling

Tang, Wai Ying Yvonne; Beckett, Alison J.; Prior, Ian A.; Coulson, Judy M.; Urbé, Sylvie; Clague, Michael J.

doi:10.1016/j.celrep.2014.08.026

Cited by 12 publications

(13 citation statements)

References 28 publications

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“…The observed pERK signal in this phase varies between published studies using population level measurements, with some reporting a rapid down-regulation of pERK in MCF10A cells stimulated with saturating EGF (48,51) and others reporting a more sustained response (52,53). We attribute these differences to variation in the frequency at which EGFR is restimulated, either by the continuous presence of EGF or by autocrine EGF ligand signaling.…”

Section: Discussioncontrasting

confidence: 49%

Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses

Sparta

Pargett

Minguet

et al. 2015

Journal of Biological Chemistry

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Background:In individual cells, EGF stimulation results in sporadic pulses of ERK activity. Results: ERK pulses are disrupted upon stimulation by alternate receptors or inhibition of EGFR. Conclusion: ERK activity pulses are generated at the level of EGFR. Significance: The dynamics of ERK activity, which control cellular proliferation and gene expression, are inconsistent with models that rely on downstream feedback.

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Section: Discussioncontrasting

confidence: 49%

Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses

Sparta

Pargett

Minguet

et al. 2015

Journal of Biological Chemistry

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“…Such significant impact of EGF-withdrawal on morphology has been shown to foster interdigitating desmosome formation due to actin remodeling in both MCF10A and HMT-3522-S1 monolayer. Moreover, those interdigitating structures were functionally linked to enhanced mechanical cell-cluster stability [ 22 ]. Of note, even after EGF depletion MCF10A acini continued to grow for several days, which could be related to the suggested growth factor reservoir and delivery function of BM scaffolds [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

The Acinar Cage: Basement Membranes Determine Molecule Exchange and Mechanical Stability of Human Breast Cell Acini

et al. 2015

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The biophysical properties of the basement membrane that surrounds human breast glands are poorly understood, but are thought to be decisive for normal organ function and malignancy. Here, we characterize the breast gland basement membrane with a focus on molecule permeation and mechanical stability, both crucial for organ function. We used well-established and nature-mimicking MCF10A acini as 3D cell model for human breast glands, with ether low- or highly-developed basement membrane scaffolds. Semi-quantitative dextran tracer (3 to 40 kDa) experiments allowed us to investigate the basement membrane scaffold as a molecule diffusion barrier in human breast acini in vitro. We demonstrated that molecule permeation correlated positively with macromolecule size and intriguingly also with basement membrane development state, revealing a pore size of at least 9 nm. Notably, an intact collagen IV mesh proved to be essential for this permeation function. Furthermore, we performed ultra-sensitive atomic force microscopy to quantify the response of native breast acini and of decellularized basement membrane shells against mechanical indentation. We found a clear correlation between increasing acinar force resistance and basement membrane formation stage. Most important native acini with highly-developed basement membranes as well as cell-free basement membrane shells could both withstand physiologically relevant loads (≤ 20 nN) without loss of structural integrity. In contrast, low-developed basement membranes were significantly softer and more fragile. In conclusion, our study emphasizes the key role of the basement membrane as conductor of acinar molecule influx and mechanical stability of human breast glands, which are fundamental for normal organ function.

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“…MCF-10A cells were grown in Dulbecco's Modified Eagle Medium: Nutrient mixture F12 (DMEM/F12) supplemented with 5% horse serum, 20 ng/mL epidermal growth factor (EGF), 0.5 µg/mL hydrocortisone, 100 ng/mL cholera toxin and 10 µg/mL insulin 26. HeLa cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

Wymant¹,

Hiscox²,

Westwell³

et al. 2016

J. Cancer

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Breast Cancer Associated gene 2 (BCA2) is an E3 ubiquitin ligase that is over-expressed in >50% of primary breast cancers, and has been shown to increase in vitro cell proliferation and invasion. The protein has been linked to alterations in EGFR degradation; however there is some dispute as to its role and influence on the biology of this receptor. Our work aimed to ascertain the role of BCA2 in EGFR endocytosis and down-regulation and to examine its links with breast cancer outcome. Data generated with the online expression analysis tool KM-Plotter showed that high BCA2 levels are associated with poor prognosis in ovarian, gastric and breast cancer, particularly HER2 over-expressing breast cancers. Experimentally, we demonstrate that over-expression of BCA2 induced a reduction in total EGFR levels. BCA2 over-expressing cells stimulated with EGF exhibited reduced lysosomal degradation of both this ligand and its receptor. Signalling downstream of EGFR in BCA2 over-expressing cells was characterized by a lower magnitude but increased duration. Our findings support a role for BCA2 in receptor endocytosis. Consistent with this we show that BCA2 over-expression reduces the level of vesicle-associated Rab7, a regulator of late endocytosis and documented interaction partner of BCA2. Levels of transferrin receptor and the uptake of transferrin were unaltered by over-expression of BCA2 indicating that trafficking changes may be limited to late endocytic sorting events. This report offers a thorough exploration of BCA2 biology and suggests a context-dependent role for the protein in the endocytic regulation of EGFR and as a prognostic biomarker in cancer.

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Plasticity of Mammary Cell Boundaries Governed by EGF and Actin Remodeling

Cited by 12 publications

References 28 publications

Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses

Receptor Level Mechanisms Are Required for Epidermal Growth Factor (EGF)-stimulated Extracellular Signal-regulated Kinase (ERK) Activity Pulses

The Acinar Cage: Basement Membranes Determine Molecule Exchange and Mechanical Stability of Human Breast Cell Acini

The Role of BCA2 in the Endocytic Trafficking of EGFR and Significance as a Prognostic Biomarker in Cancer

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