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Selective small molecule Stat3 inhibitor reduces breast cancer tumor-initiating cells and improves recurrence free survival in a human-xenograft model.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (8), pp. e30207. Date of Electronic Publication: 2012 Aug 06. - Publication Year :
- 2012
-
Abstract
- Metastasis and disease relapse are hypothesized to result from tumor initiating cells (TICs). Previously, we have defined a CD44+/CD24-/low mammosphere-forming tumorigenic 493-gene signature in breast cancer. Stat3 was identified as a critical node in self-renewal based on an ongoing lentiviral shRNA screen being conducted in two breast cancer cell lines SUM159 and BT549. In corroborating work, targeting the SH2 domain of Stat3 with a novel small molecule decreased the percentage of cells expressing TIC markers (CD44+/CD24-/low and ALDH+) and mammosphere formation in p-Stat3 overexpressing human breast cancer xenografts in SCID-beige mice. Importantly, we observed a four-fold improvement in the 30-day recurrence-free survival relative to docetaxel alone with the addition of the Stat3 inhibitor in the chemoresistant tumor model. Thus, these findings provide a strong impetus for the development of selective Stat3 inhibitors in order to improve survival in patients with p-Stat3 overexpressing tumors.
- Subjects :
- Adipose Tissue drug effects
Animals
Breast Neoplasms drug therapy
Cell Line, Tumor
Cell Proliferation drug effects
Disease Models, Animal
Disease-Free Survival
Docetaxel
Drug Resistance, Neoplasm drug effects
Female
Humans
Kaplan-Meier Estimate
Mice
Mice, SCID
Neoplasm Recurrence, Local
Neoplastic Stem Cells drug effects
Neoplastic Stem Cells metabolism
STAT3 Transcription Factor metabolism
Small Molecule Libraries therapeutic use
Taxoids pharmacology
Taxoids therapeutic use
Time Factors
Tumor Burden drug effects
Breast Neoplasms pathology
Neoplastic Stem Cells pathology
STAT3 Transcription Factor antagonists & inhibitors
Small Molecule Libraries pharmacology
Xenograft Model Antitumor Assays
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22879872
- Full Text :
- https://doi.org/10.1371/journal.pone.0030207