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

Jillian E. Koziel, Brittney Shea Herbert

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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>+</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>+</sup> breast cancer cell lines. The effects of imetelstat on CSC populations of HER2<sup>+</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.

Original languageEnglish (US)
Pages (from-to)607-618
Number of pages12
JournalBreast Cancer Research and Treatment
Volume149
Issue number3
DOIs
StatePublished - Jan 1 2015

Fingerprint

Neoplastic Stem Cells
Telomerase
Breast Neoplasms
Population
Neoplasms
imetelstat
Cell Self Renewal
Trastuzumab
Telomere Shortening
Recurrence
Telomere
Heterografts
Oligonucleotides
Flow Cytometry
Stem Cells
Neoplasm Metastasis
Phenotype

Keywords

  • Breast cancer
  • Cancer stem cells
  • HER2<sup>+</sup>
  • Telomerase
  • Trastuzumab

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells",
abstract = "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+ 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+ breast cancer cell lines. The effects of imetelstat on CSC populations of HER2+ 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.",
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T1 - The telomerase inhibitor imetelstat alone, and in combination with trastuzumab, decreases the cancer stem cell population and self-renewal of HER2+ breast cancer cells

AU - Koziel, Jillian E.

AU - Herbert, Brittney Shea

PY - 2015/1/1

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N2 - 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+ 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+ breast cancer cell lines. The effects of imetelstat on CSC populations of HER2+ 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.

AB - 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+ 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+ breast cancer cell lines. The effects of imetelstat on CSC populations of HER2+ 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.

KW - Breast cancer

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KW - Telomerase

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