Dataset Information

Proteomics of extracellular matrix from eIF4E deficient mouse mammary fat pad

ABSTRACT: It was demonstrated that mice with eIF4E that cannot be activated by phosphorylation (S209A) produced extracellular matrix (ECM) less conducive to breast cancer tumor invasion and metastasis. To examine whether this could in part bedue to differences in the protein composition we analyzed the proteome of soluble and insoluble ECM fractions derived from the mammary fat pad of mice with either WT or constitutively inactivated (S209A or "KI") eIF4E.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Mammary Epithelium

DISEASE(S): Breast Cancer

SUBMITTER: Vincent Richard

LAB HEAD: Christoph H. Borchers

PROVIDER: PXD028953 | Pride | 2022-08-12

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	QE001790_VR_Sonia_BalbC_WT_Sol_1.raw	Raw
	QE001791_VR_Sonia_BalbC_KI_Sol_1.raw	Raw
	QE001795_VR_Sonia_BalbC_KI_Sol_2.raw	Raw
	QE001797_VR_Sonia_BalbC_WT_Sol_2.raw	Raw
	QE001802_VR_Sonia_BalbC_KI_Sol_3.raw	Raw

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Publications

Phosphorylation of eIF4E in the stroma drives the production and spatial organisation of collagen type I in the mammary gland.

Preston Samuel E J SEJ Bartish Margarita M Richard Vincent R VR Aghigh Arash A Gonçalves Christophe C Smith-Voudouris Julian J Huang Fan F Thébault Paméla P Cleret-Buhot Aurélie A Lapointe Réjean R Légaré François F Postovit Lynne-Marie LM Zahedi René P RP Borchers Christoph H CH Miller Wilson H WH Del Rincón Sonia V SV

Matrix biology : journal of the International Society for Matrix Biology 20220714

The extracellular matrix (ECM) plays critical roles in breast cancer development. Whether ECM composition is regulated by the phosphorylation of eIF4E on serine 209, an event required for tumorigenesis, has not been explored. Herein, we used proteomics and mouse modeling to investigate the impact of mutating serine 209 to alanine on eIF4E (i.e., S209A) on mammary gland (MG) ECM. The proteomic data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dat ...[more]

PMID: 35842012

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Project description:Translation initiation factor eIF4E is overexpressed early in breast cancers in association with disease progression and reduced survival. Much remains to be understood regarding the role of eIF4E in human cancer. Using immortalized human breast epithelial cells, we report that elevated expression of elF4E translationally activates the TGFβ pathway, promoting cell invasion, loss of cell polarity, increased cell survival and other hallmarks of early neoplasia. Overexpression of eIF4E is shown to facilitate selective translation of integrin β1 mRNA, which drives the translationally controlled assembly of a TGFβ receptor signaling complex containing α3β1 integrins, β-catenin, TGFβ receptor I, E-cadherin and phosphorylated Smads2/3. This receptor complex acutely sensitizes non-malignant breast epithelial cells to activation by typically sub-stimulatory levels of activated TGFβ. TGFβ can promote cellular differentiation or invasion and transformation. As a translational coactivator of TGFβ, eIF4E confers selective mRNA translation, reprogramming non-malignant cells to an invasive phenotype by reducing the set-point for stimulation by activated TGFβ. Overexpression of eIF4E may be a pro-invasive facilitator of TGFβ activity. MCF10A cells were subjected to consitutive silencing with a non-silencing control shRNA or an shRNA to eIF4E. Total RNA, light polysomal RNA (2-3 ribosome fraction) and heavy polysomal RNA (greater than or equal to 4 ribosome fraction) were purified and used for hybridization to Affymetrix 133 2.0 Plus arrays. Data analysis was conducted using MicroArray Suite Software from Affymetrix. To remove probe sets with insignificant differences between perfect match and mismatch data, which creates a more robust data set of greater clarity without a high level of background noise, discrimination values for each probe pair were calculated for low intensity ratios using Wilcoxon signed rank test to assess significance and data re-assigned as either changed or unchanged mRNAs. Data sets were compared using Expressionist Suite software. Significance of mRNAs were assessed using fold changes and the FDRs estimated based on t-tests.

Project description:Accumulating data indicate translation plays a role in cancer biology, particularly its rate limiting stage of initiation. Despite this evolving recognition, the function and importance of specific translation initiation factors is unresolved. The eukaryotic translation initiation complex eIF4F consists of eIF4E and eIF4G at a 1:1 ratio. Although it is expected that they display interdependent functions, several publications suggest independent mechanisms. This study is the first to directly assess the relative contribution of eIF4F components to the expressed cellular proteome, transcription factors, microRNAs, and phenotype in a malignancy known for extensive protein synthesis- multiple myeloma (MM). Previously, we have shown that eIF4E/eIF4GI attenuation (siRNA/ Avastin) deleteriously affected MM cells' fate and reduced levels of eIF4E/eIF4GI established targets. Here, we demonstrated that eIF4E/eIF4GI indeed have individual influences on cell proteome. We used an objective, high throughput assay of mRNA microarrays to examine the significance of eIF4E/eIF4GI silencing to several cellular facets such as transcription factors, microRNAs and phenotype. We showed different imprints for eIF4E and eIF4GI in all assayed aspects. These results promote our understanding of the relative contribution and importance of eIF4E and eIF4GI to the malignant phenotype and shed light on their function in eIF4F translation initiation complex. This study concentrated on a particular cancer model and studied the role of eIF4E and eIF4GI in the design of the cells' proteome. We used an unbiased, high throughput system to evaluate the individual importance of eIF4E and eIF4GI levels in MM. We used models of eIF4E or eIF4GI knocked down (KD) MM cell line RPMI 8226 and profiled their respective translated transcription factors (TF), often tumor suppressors or oncogenes. Furthermore, we assessed the KDs' microRNAs repertoires and cells' phenotype. Significant differences were observed between eIF4E and eIF4GI knockdown imprints.