TY - JOUR
T1 - Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration
AU - Thomas, Z. I.
AU - Gibson, W.
AU - Sexton, J. Z.
AU - Aird, K. M.
AU - Ingram, S. M.
AU - Aldrich, A.
AU - Lyerly, H. K.
AU - Devi, G. R.
AU - Williams, K. P.
N1 - Funding Information:
This study was supported by NIH grant CA137844 (KP Williams) and American Cancer Society Grant RSG-08-290-01-CCE (GR Devi) and DOD predoctoral award (KM Aird) with additional funding from the Golden LEAF Foundation and the BIOIMPACT Initiative of the State of North Carolina. We thank Ginger Smith (BRITE, NCCU) and Shannon Peplinski (Duke University Medical Center) for technical assistance.
PY - 2011/5/10
Y1 - 2011/5/10
N2 - 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.
AB - 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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U2 - 10.1038/bjc.2011.133
DO - 10.1038/bjc.2011.133
M3 - Article
C2 - 21505458
AN - SCOPUS:79955797797
SN - 0007-0920
VL - 104
SP - 1575
EP - 1586
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 10
ER -