Journal
CANCER RESEARCH
Volume 69, Issue 5, Pages 1706-1711Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-08-2351
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Funding
- National Cancer Institute [2RO1-CA077337]
- American Cancer Society [RSG-02-144-01]
- Department of Defense/Breast [Predoctoral Fellowship]
- Department of Homeland Security ORISE
- Cancer Program [DAMD-17-03-1-0578, DAMD-W81XWH-08-1-0390]
- Georgia Cancer Coalition [Distinguished Cancer Scholar]
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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 TMS-1 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 epithelia] cells. siRNA-mediated knockdown of TMSI 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 TMS1. These data show 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 down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions. [Cancer Res 2009;69(5): 1706-11]
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