Journal
PLOS ONE
Volume 10, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0117097
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Funding
- National Cancer Institute Cancer Center Breast Cancer SPORE at University of Chicago [P50 CA125183-05]
- American Cancer Society Illinois Division
- Breast Cancer Research Foundation [634366]
- Jianghan Univesity [101006850001]
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Our previous data illustrated that activation of the canonical Wnt signaling pathway was enriched in triple-negative breast cancer and associated with reduced overall survival in all patients. To determine whether Wnt signaling may be a promising therapeutic target for triple-negative breast cancer, we investigated whether beta-catenin was necessary for tumorigenic behaviors in vivo and in vitro. beta-catenin expression level was significantly reduced in two human triple-negative breast cancer cell lines, MDA-MB-231 and HCC38, using lentiviral delivery of beta-catenin-specific small hairpin RNAs (shRNAs). Upon implantation of the cells in the mammary fat pad of immunocompromised mice, we found that beta-catenin shRNA HCC38 cells formed markedly smaller tumors than control cells and grew much more slowly. In in vitro assays, beta-catenin silencing significantly reduced the percentage of Aldefluor-positive cells, a read-out of the stem-like cell population, as well as the expression of stem cell-related target genes including Bmi-1 and c-Myc. beta-catenin-knockdown cells were also significantly impaired in their ability to migrate in wound-filling assays and formanchorage-independent colonies in soft agar. beta-catenin-knockdown cells were more sensitive to chemotherapeutic agents doxorubicin and cisplatin. Collectively, these data suggest that beta-catenin is required for triple-negative breast cancer development by controlling numerous tumor-associated properties, such as migration, stemness, anchorage-independent growth and chemosensitivity.
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