Title

Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin

UMMS Affiliation

Department of Cell and Developmental Biology

Date

5-8-2014

Document Type

Article

Disciplines

Cancer Biology

Abstract

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPβ expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPβ-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.

Rights and Permissions

Citation: Damiano L, Stewart KM, Cohet N, Mouw JK, Lakins JN, Debnath J, Reisman D, Nickerson JA, Imbalzano AN, Weaver VM. Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin. Oncogene. 2014 May 8;33(19):2441-53. doi: 10.1038/onc.2013.220. Link to article on publisher's website

Related Resources

Link to article in PubMed

Keywords

α5 integrin, Brahma, breast cancer, C/EBPβ, ECM–cell interactions, c-Myc

PubMed ID

23770848