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

• Type of Material: Article
• Authors: Melissa J. Parsons, Emory University; Pritty Patel, Emory University; Daniel J Brat, Emory University; Laronna Colbert, Emory University; Paula M. Vertino, Emory University
• Language: English
• Date: 2009-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009, American Association for Cancer Research
• Final Published Version (URL): http://cancerres.aacrjournals.org/content/69/5/1706
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 69
• Issue: 5
• Start Page: 1706
• End Page: 1711
• Grant/Funding Information: Supported by grants from the National Cancer Institute (2RO1-CA077337) and the American Cancer Society (RSG-02-144-01) to PMV, a Predoctoral fellowship from the Department of Defense/Breast Cancer Program fellowship (DAMD-17-03-1-0578) to MJP and a Department of Homeland Security ORISE and Department of Defense/Breast Cancer Program (DAMD-W81XWH-08-1-0390) fellowships to PP. P.M.V is a Georgia Cancer Coalition Distinguished Cancer Scholar
• Keywords: caspase-8; Bim; DCIS; apoptosis; breast cancer
• Research Categories: Health Sciences, Oncology

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 TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown. Here we examined the role of TMS1 in anoikis. We found that TMS1 expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of ERK and an impaired ability to upregulate 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 TMS1. These data demonstrate a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 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 TMS1 is selectively downregulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions.