Silencing of TMS1/ASC promotes resistance to anoikis in breast epithelial cells

Melissa J. Parsons, Pritty Patel, Daniel J. Brat, Laronna Colbert, Paula M. Vertino

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact. In normal epithelial cells, the loss of such contact triggers a form of apoptosis known as detachment-induced apoptosis or "anoikis." TMS1/ASC is a bipartite adaptor molecule that participates in inflammatory and apoptotic signaling pathways. Epigenetic silencing of TMSl has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMSl silencing contributes to carcinogenesis is unknown. Here, we examined the role of TMSl in anoikis. We found that TMSl expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA mediated knockdown of TMSl leads to anoikis resistance, due in part to the persistent activation of extracellular signal-regulated kinase and an impaired ability to up-regulate the BH3-only protein Bim. We further show that the detachment-induced cleavage of procaspase-8, a newly described mediator of cellular adhesion, is significantly inhibited in the absence of TMSl. These data show a novel upstream role for TMSl in the promotion of anoikis, and suggest that silencing of TMSl may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development. This conclusion is supported by in vivo data showing that TMSl is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions.

Original languageEnglish (US)
Pages (from-to)1706-1711
Number of pages6
JournalCancer Research
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2009

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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