Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells
Abstract
Disruption of apoptosis may allow metastatic cell survival and confer resistance to chemotherapeutic drugs. We have analysed the molecular pathways that activate these survival genes in specific sites of metastasis. Estrogen receptor-negative breast cancer cell line MDA-MB435 and two metastatic sublines derived from lung (435L) and brain (435B) were analysed for the expression of members of the Bcl-2 family of apoptosis regulators. The levels of Bcl-2 were higher in the metastatic sublines than in parental cells, which correlated with the activation of Stat3, but not with the expression and/or activation of known bcl-2 transcription factors (CREB and WT1). In the brain subline, both expression of Bcl-2 and Stat3 activation were induced by epidermal growth factor and abrogated after treatment with kinase inhibitors specific for epidermal growth factor receptor or Jak2. Furthermore, transfection of 435B with a dominant-negative Stat3 markedly reduced the expression of Bcl-2 protein, whereas transient expression of a constitutively active Stat3 increased Bcl-2 in parental 435 cells. In addition, blockade of Stat3 activation by treatment with epidermal growth factor receptor and Jak2 kinase inhibitors or transfection with a dominant negative Stat3, sensitizes 435B cells to chemotherapy-induced apoptosis. Our data suggest that an increased activation of the Stat3-Bcl-2 pathway in estrogen receptor-negative metastatic breast cancer cell lines confer a survival advantage to these ce…
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STAT3-mediated Bcl-2 expression in metastatic subclones of MDA-MB435 correlates with increased pSTAT3 and contributes to chemoresistance.
“STAT3-mediated Bcl-2 expression in metastatic subclones of the parental cell line MDA-MB435 (estrogen receptor-negative breast cancer) correlates with increased pSTAT3, but not with other transcription factors that regulate Bcl-2, and contributes to chemoresistance in this cell line, suggesting that the antiapoptotic effects of STAT3 contribute to treatment sensitivity.80”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [80]
Overactivation of STAT3 is associated with resistance to EGFR-targeted therapies in several cancers, including HNSCC, bladder cancer, and others.
“For example, overactivation of STAT3 is associated with resistance to EGFR-targeted therapies in several cancers, including HNSCC, bladder cancer, and others.40,80”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [80]
STAT3 is implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition restores sensitivity of tumors to chemotherapeutic drugs.
“STAT3 has been implicated in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs”
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 Real et al., 2002
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Corvinus, F. M., Orth, C., Moriggl, R., Tsareva, S. A., Wagner, S., Pfitzner, E. B., Baus, D., Kaufman, R., Huber, L. A., Zatloukal, K., et al. (2005) · Neoplasia · doi:10.1593/neo.04571 · Cited by 427 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…in chemotherapy resistance; there is a strong correlation between STAT3 activation and chemoresistance, and STAT3 inhibition has been shown to restore sensitivity of tumors to chemotherapeutic drugs (Real et al., 2002; Huang et al., 2012; Sims et al., 2013; Lee et al., 2014; Zhao et al., 2016).”
BackgroundZhang, X., Yue, P., Fletcher, S., Zhao, W., Gunning, P. T., & Turkson, J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.01.001 · Cited by 179 · see citing works
STAT3 positively regulates an early step in B-cell development
Chou, W.-C., Levy, D. E., & Lee, C.-K. (2006) · Blood · doi:10.1182/blood-2006-05-024430 · Cited by 94 · see citing works
Critical analysis of the potential for targeting STAT3 in human malignancy
Grandis, J., & Peyser (2013) · OncoTargets and Therapy · doi:10.2147/ott.s47903 · Cited by 24 · see citing works
“For example, overactivation of STAT3 is associated with resistance to EGFR-targeted therapies in several cancers, including HNSCC, bladder cancer, and others.(40,80) Biopsies of recurrent HNSCC following treatment with cetuximab, a Food and Drug Administration-approved monoclonal antibody targeting EGFR, exhibit eleva…”
- Authors
- Real, P. J., Sierra, A., de Juan, A., Segovia, J. C., Lopez-Vega, J. M., & Fernandez-Luna, J. L.
- Affiliations
- Marqués de Valdecilla University Hospital (ES)
- Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (ES)
- Venue
- Oncogene
- Published
- 2002-10-25
- Volume
- 21
- Issue
- 50
- Pages
- 7611-7618
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2069657245
- Cited by
- 321
- References
- 0
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 12 · 2023: 11 · 2022: 7 · 2021: 16 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 20 · 2016: 23 · 2015: 15 · 2014: 23 · 2013: 16 · 2012: 19
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- STAT3, Bcl-2, chemoresistance, metastatic breast cancer, estrogen receptor-negative breast cancer, apoptosis, epidermal growth factor receptor, JAK2, dominant-negative STAT3, brain metastases, lung metastasis, CREB, WT1
- MeSH terms
- Antineoplastic Agents, Brain Neoplasms, Breast Neoplasms, Carcinoma, DNA-Binding Proteins, Enzyme Inhibitors, Female, Humans, Lung Neoplasms, Neoplasm Metastasis, Neoplasms, Hormone-Dependent, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Receptors, Estrogen, Transcription, Genetic, Tumor Cells, Cultured, Trans-Activators, Apoptosis, Cyclic AMP Response Element-Binding Protein, Proto-Oncogene Proteins c-bcl-2, Tyrphostins, STAT3 Transcription Factor, bcl-X Protein, Janus Kinase 2, ErbB Receptors
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