Journal
STEM CELLS
Volume 30, Issue 11, Pages 2366-2377Publisher
WILEY
DOI: 10.1002/stem.1219
Keywords
Breast cancer stem cells; Histone deacetylase inhibitors; Dedifferentiation; ss-Catenin
Categories
Funding
- National Institute of Health [R01CA138239-01]
- Susan G. Komen Breast Cancer Foundation [KG081287]
- State of Texas Grant for Rare and Aggressive Cancers
- University of Texas M.D. Anderson Cancer Center Institutional Research Grant
- University of Texas Health Sciences Center [KL2 RR024149]
Ask authors/readers for more resources
Recent studies have shown that differentiated cancer cells can dedifferentiate into cancer stem cells (CSCs) although to date no studies have reported whether this transition is influenced by systemic anti-cancer agents. Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that promotes self-renewal and expansion of hematopoietic stem cells and facilitates the generation of induced pluripotent stem cells from somatic cells and is currently being investigated in breast cancer clinical trials. We hypothesized that HDAC inhibitors reprogram differentiated cancer cells toward the more resistant stem cell-like state. Two highly aggressive breast cancer cell lines, SUM159 and MDA-231, were sorted based on aldehyde dehydrogenase (ALDH) activity and subsequently ALDH-negative and ALDH-positive cells were treated with one of two known HDAC inhibitors, VA or suberoylanilide hydroxamic acid. In addition, primary tumor cells from patients with metastatic breast cancer were evaluated for ALDH activity following treatment with HDAC inhibitors. We demonstrate that single-cell-sorted ALDH-negative cells spontaneously generated ALDH-positive cells in vitro. Treatment of ALDH-negative cells with HDAC inhibitors promoted the expansion of ALDH-positive cells and increased mammosphere-forming efficiency. Most importantly, it significantly increased the tumor-initiating capacity of ALDH-negative cells in limiting dilution outgrowth assays. Moreover, while HDAC inhibitors upregulated beta-catenin expression and significantly increased WNT reporter activity, a TCF4 dominant negative construct abolished HDAC-inhibitor-induced expansion of CSCs. These results demonstrate that HDAC inhibitors promote the expansion of breast CSCs through dedifferentiation and have important clinical implications for the use of HDAC inhibitors in the treatment of cancer. STEM CELLS2012;30:23662377
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available