Re-Writing the Histone Code of Breast Cancer Stem Cells
Abstract
The transcription factor SOX2 is a Cancer Stem Cell (CSC) marker that plays an pivotal role maintaining self-renewal in both embryonic and adult breast stem cells. In human embryonic stem cells SOX2 expression is down regulated by means of epigenetic mechanisms, including DNA methylation. SOX2 is overexpressed in many breast cancer cell lines as well as in poorly differentiated triple negative breast tumor specimens. Thus, enforced down-regulation of SOX2 in tumor cells offers a unique therapeutic opportunity to suppress breast cancer cell self-renewal and tumor initiation. Epigenetic mechanisms, such as DNA methylation, are inherited during cell division and result in permanent and stable silencing. We have generated arrays of Artifical Transcription Factors (ATFs) made of specific six-zinc finger domains (ZF) targeting unique 18-base pair sites in the SOX2 promoter. The 6ZFs were linked to the repressor domain Krueppel Associated Box (KRAB) domain or DNA methyltransferase 3a (DNMT3a) catalytic domain and expressed in aggressive MDA-MB-435s breast cancer cells using retroviral vectors. Our results show that two ATFs were able to silence SOX2 mRNA and protein levels with virtually 100% down-regulation. This was accompanied with a potent suppression of both tumor cell proliferation and anchorage independent growth. These epigenetic switches represent a promising therapeutic strategy to effectively target breast cancer stem cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2011
- Accession Number
- ADA554292
Entities
People
- Brian D Strahl
- Pilar Blancafort
Organizations
- University of North Carolina at Chapel Hill