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- W1979394535 abstract "Cancer relapse following treatment remains a significant barrier to achieving cures for many patients. An emerging framework for addressing this problem focuses on cancer stem cells (CSCs). Clinical and preclinical data suggest that CSCs survive chemotherapy and antiangiogenic therapy. In breast cancer, CSCs are marked by the cell surface expression of CD44, the major receptor for hyaluronic acid. The SKBR3 cell line was previously shown to be a clinically relevant model of breast CSCs in vivo, and we have further developed this model to enable mechanistic studies of tumor relapse in vitro. We found that chemotherapy and hypoxia both enriched for CD44 hi populations in SKBR3, but surprisingly, the populations were phenotypically distinct. CD44 hi cells from chemotherapy but not hypoxia exhibited increased tumor cell growth and increased sensitivity to the CSC-specific inhibitor salinomycin, compared to CD44 lo cells. To examine these CD44 hi and CD44 lo populations further, we performed transcriptional profiling with sorted cells. We found that the growth factor TGF beta-2 was upregulated in chemotherapy-treated CD44 hi cells and also enhanced the growth of these cells, which suggests that TGF beta-2 autocrine/paracrine signaling can promote the growth of surviving cells. We also observed an increase in xCT (SLC7A11) expression upon chemotherapy treatment and identified the CD44v8-10 variant expressed in the CD44 hi SKBR3. CD44v could therefore stabilize xCT and promote survival by lowering intracellular reactive oxygen species (ROS). We have also established a functional role for CD44 in SKBR3 cell growth: CD44 knockdown prevented colony formation, and conversely the CD44 ligand hyaluronic acid enhanced colony formation. These findings indicate that CD44 not only marks CSC populations that arise in response to chemotherapy but also functions in their survival. Our work suggests that mechanisms of tumor relapse vary based on the particular therapy, and defining these mechanisms will allow for the development of novel therapeutic strategies to enable long-term responses in the clinic. Citation Format: Siobhan O9Brien, Liang Chen, Wenyan Zhong, Douglas Armellino, Maximillian Follettie, Marc Damelin. Breast cancer cells escape from chemotherapy and hypoxia by distinct mechanisms. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1968. doi:10.1158/1538-7445.AM2014-1968" @default.
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- W1979394535 date "2014-09-30" @default.
- W1979394535 modified "2023-10-06" @default.
- W1979394535 title "Abstract 1968: Breast cancer cells escape from chemotherapy and hypoxia by distinct mechanisms" @default.
- W1979394535 doi "https://doi.org/10.1158/1538-7445.am2014-1968" @default.
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