Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration

Z. I. Thomas, W. Gibson, J. Z. Sexton, Katherine Aird, S. M. Ingram, A. Aldrich, H. K. Lyerly, G. R. Devi, K. P. Williams

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Background:Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients.Methods:The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays.Results:Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement.Conclusion:Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.

Original languageEnglish (US)
Pages (from-to)1575-1586
Number of pages12
JournalBritish Journal of Cancer
Volume104
Issue number10
DOIs
StatePublished - May 10 2011

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Inflammatory Breast Neoplasms
Apoptosis
Cell Movement
Cell Line
Cell Migration Assays
Cell Proliferation
Breast Neoplasms
Annexin A5
Gene Expression Profiling
Wound Healing
Small Interfering RNA
Cell Survival
Down-Regulation
Genes
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Thomas, Z. I., Gibson, W., Sexton, J. Z., Aird, K., Ingram, S. M., Aldrich, A., ... Williams, K. P. (2011). Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. British Journal of Cancer, 104(10), 1575-1586. https://doi.org/10.1038/bjc.2011.133
Thomas, Z. I. ; Gibson, W. ; Sexton, J. Z. ; Aird, Katherine ; Ingram, S. M. ; Aldrich, A. ; Lyerly, H. K. ; Devi, G. R. ; Williams, K. P. / Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. In: British Journal of Cancer. 2011 ; Vol. 104, No. 10. pp. 1575-1586.
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abstract = "Background:Inflammatory breast cancer (IBC) is an aggressive subtype of breast cancer with distinct molecular profiles. Gene expression profiling previously identified sonic hedgehog (SHH) as part of a gene signature that is differentially regulated in IBC patients.Methods:The effects of reducing GLI1 levels on protein expression, cell proliferation, apoptosis and migration were determined by immunoblots, MTT assay, Annexin-V/PI assay and conventional and automated cell migration assays.Results:Evaluation of a panel of breast cancer cell lines revealed elevated GLI1 expression, typically a marker for hedgehog-pathway activation, in a triple-negative, highly invasive IBC cell line, SUM149 and its isogenic-derived counterpart rSUM149 that has acquired resistance to ErbB1/2 targeting strategies. Downregulation of GLI1 expression in SUM149 and rSUM149 by small interfering RNA or a small molecule GLI1 inhibitor resulted in decreased proliferation and increased apoptosis. Further, GLI1 suppression in these cell lines significantly inhibited cell migration as assessed by a wound-healing assay compared with MCF-7, a non-invasive cell line with low GLI1 expression. A novel high-content migration assay allowed us to quantify multiple effects of GLI1 silencing including significant decreases in cell distance travelled and linearity of movement.Conclusion:Our data reveal a role for GLI1 in IBC cell proliferation, survival and migration, which supports the feasibility of targeting GLI1 as a novel therapeutic strategy for IBC patients.",
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Thomas, ZI, Gibson, W, Sexton, JZ, Aird, K, Ingram, SM, Aldrich, A, Lyerly, HK, Devi, GR & Williams, KP 2011, 'Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration', British Journal of Cancer, vol. 104, no. 10, pp. 1575-1586. https://doi.org/10.1038/bjc.2011.133

Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. / Thomas, Z. I.; Gibson, W.; Sexton, J. Z.; Aird, Katherine; Ingram, S. M.; Aldrich, A.; Lyerly, H. K.; Devi, G. R.; Williams, K. P.

In: British Journal of Cancer, Vol. 104, No. 10, 10.05.2011, p. 1575-1586.

Research output: Contribution to journalArticle

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T1 - Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration

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AU - Gibson, W.

AU - Sexton, J. Z.

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AU - Ingram, S. M.

AU - Aldrich, A.

AU - Lyerly, H. K.

AU - Devi, G. R.

AU - Williams, K. P.

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