The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of [HER2.sup.+] breast cancer cells

Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for [HER2.sup.+] breast cancers. Telomerase is reactivate...

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Bibliographic Details
Published in:Breast cancer research and treatment 2015-02, p.607
Main Authors: Koziel, Jillian E, Herbert, Brittney-Shea
Format: Article
Language:English
Subjects:
Antimitotic agents
Antineoplastic agents
Breast cancer
Cancer
Cancer cells
Development and progression
Health aspects
Prevention
Statistics
Stem cells
Telomerase
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Summary:Cancer stem cells (CSCs) are thought to be responsible for tumor progression, metastasis, and recurrence. HER2 overexpression is associated with increased CSCs, which may explain the aggressive phenotype and increased likelihood of recurrence for [HER2.sup.+] breast cancers. Telomerase is reactivated in tumor cells, including CSCs, but has limited activity in normal tissues, providing potential for telomerase inhibition in anti-cancer therapy. The purpose of this study was to investigate the effects of a telomerase antagonistic oligonucleotide, imetelstat (GRN163L), on CSC and non-CSC populations of [HER2.sup.+] breast cancer cell lines. The effects of imetelstat on CSC populations of [HER2.sup.+] breast cancer cells were measured by ALDH activity and CD44/24 expression by flow cytometry as well as mammosphere assays for functionality. Combination studies in vitro and in vivo were utilized to test for synergism between imetelstat and trastuzumab. Imetelstat inhibited telomerase activity in both subpopulations. Moreover, imetelstat alone and in combination with trastuzumab reduced the CSC fraction and inhibited CSC functional ability, as shown by decreased mammosphere counts and invasive potential. Tumor growth rate was slower in combination-treated mice compared to either drug alone. Additionally, there was a trend toward decreased CSC marker expression in imetelstat-treated xenograft cells compared to vehicle control. Furthermore, the observed decrease in CSC marker expression occurred prior to and after telomere shortening, suggesting that imetelstat acts on the CSC subpopulation in telomere length-dependent and -independent mechanisms. Our study suggests addition of imetelstat to trastuzumab may enhance the effects of HER2 inhibition therapy, especially in the CSC population. Keywords Telomerase * Breast cancer * [HER2.sup.+] * Cancer stem cells Trastuzumab
ISSN:0167-6806
DOI:10.1007/s10549-015-3270-1