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Cited by 563Cytokine Signaling Pathways and InteractionsCell death mechanisms and regulationBreast Cancer Treatment Studies

Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells

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Gritsko, Tanya, Williams, Ann, Turkson, James, Kaneko, Satoshi, Bowman, Tammy, Huang, Mei, Nam, Sangkil, Eweis, Ibrahim +11 more·2006·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-04-1752
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Abstract

PURPOSE: Signal transducer and activator of transcription 3 (Stat3) protein is persistently activated in breast cancer and promotes tumor cell survival. To gain a better understanding of the role of constitutive Stat3 signaling in breast cancer progression, we evaluated the expression profile of potential Stat3-regulated genes that may confer resistance to apoptosis. EXPERIMENTAL DESIGN: Stat3 signaling was blocked with antisense oligonucleotides in human MDA-MB-435s breast cancer cells and Affymetrix GeneChip microarray analysis was done. The candidate Stat3 target gene Survivin was further evaluated in molecular assays using cultured breast cancer cells and immunohistochemistry of breast tumor specimens. RESULTS: Survivin, a member of the inhibitor of apoptosis protein family, was identified as a potential Stat3-regulated gene by microarray analysis. This was confirmed in Survivin gene promoter studies and chromatin immunoprecipitation assays showing that Stat3 directly binds to and regulates the Survivin promoter. Furthermore, direct inhibition of Stat3 signaling blocked the expression of Survivin protein and induced apoptosis in breast cancer cells. Direct inhibition of Survivin expression also induced apoptosis. Increased Survivin protein expression correlates significantly (P = 0.001) with elevated Stat3 activity in primary breast tumor specimens from high-risk patients who were resistant to chemotherapy treatment. CONCLUSIONS: We identify Survivin as a direct downstream target gene of Stat3 in human breast cancer cells that is critical for their survival in culture. Our findings suggest that activated Stat3 signaling contributes to breast cancer progression and resistance to chemotherapy by, at least in part, inducing expression of the antiapoptotic protein, Survivin.

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  • Elevated levels of STAT3 are observed in many solid and hematologic tumors, where its signaling underpins majority of cardinal features of cancer, including growth, antiapoptosis, transformation, angiogenesis, metastasis, and cancer stem cell maintenance.

    “Elevated levels of STAT3 have been observed in a large number of both solid and hematologic tumors, where its signaling underpins a majority of all known cardinal features of cancer (Yuan et al., 2015b), including growth and proliferation (Banerjee and Resat, 2016), antiapoptosis (Gritsko et al., 2006), cell transformation (Bromberg et al., 1999), angiogenesis (Doucette et al., 2012), metastasis (”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Gritsko et al., 2006

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Authors
Gritsko, T., Williams, A., Turkson, J., Kaneko, S., Bowman, T., Huang, M., Nam, S., Eweis, I., Diaz, N., Sullivan, D., Yoder, S., Enkemann, S., Eschrich, S., Lee, J.-H., Beam, C. A., Cheng, J., Minton, S., Muro-Cacho, C. A., & Jove, R.
Affiliations
  • 1Molecular Oncology,
  • 2Pathology,
  • 3Experimental Therapeutics,
  • 4Biostatistics, and
  • University of South Florida (US)
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2006-01-01
Volume
12
Issue
1
Pages
11-19
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-04-1752
OpenAlex
W2170090299
Cited by
563
References
52
Citations by year
2026: 9 · 2025: 21 · 2024: 14 · 2023: 33 · 2022: 28 · 2021: 28 · 2020: 23 · 2019: 29 · 2018: 27 · 2017: 33 · 2016: 35 · 2015: 31 · 2014: 35 · 2013: 38 · 2012: 30
FWCI
15.30
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Moffitt Cancer Center
  • National Institutes of Health
  • National Cancer Institute (R01CA055652, CA 82533, CA-55652, P01CA082533)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
STAT3 signaling, survivin, breast cancer, apoptosis resistance, STAT3 target genes, inhibitor of apoptosis proteins, chemoresistance, MDA-MB-435S cells, promoter regulation, tumor cell survival
MeSH terms
Survivin, Breast Neoplasms, Enzyme Activation, Female, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Microtubule-Associated Proteins, Neoplasm Proteins, Promoter Regions, Genetic, Blotting, Western, Gene Expression, Gene Expression Regulation, Neoplastic, Apoptosis, In Situ Nick-End Labeling, Oligonucleotide Array Sequence Analysis, Electrophoretic Mobility Shift Assay, Cell Line, Tumor, STAT3 Transcription Factor, Inhibitor of Apoptosis Proteins

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