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Cited by 89Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGrowth Hormone and Insulin-like Growth Factors

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IGFBP7 reduces breast tumor growth by induction of senescence and apoptosis pathways

Benatar, Tania, Yang, Wenyi, Amemiya, Yutaka, Evdokimova, Valentina, Kahn, Harriette, Holloway, Claire, Seth, Arun·2012·Breast Cancer Research and Treatment
DOI 10.1007/s10549-011-1816-4
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Abstract

Insulin-like growth factor binding protein 7 (IGFBP7) has been shown to be a tumor suppressor in a variety of cancers. We previously have shown that IGFBP7 expression is inversely correlated with disease progression and poor outcome in breast cancer. Overexpression of IGFBP7 in MDA-MB-468, a triple-negative breast cancer (TNBC) cell line, resulted in inhibition of growth and migration. Xenografted tumors bearing ectopic IGFBP7 expression were significantly growth-impaired compared to IGFBP7-negative controls, which suggested that IGFBP7 treatment could inhibit breast cancer cell growth. To confirm this notion, 14 human patient primary breast tumors were analyzed by qRTPCR for IGFBP7 expression. The TNBC tumors expressed the lowest levels of IGFBP7 expression, which also correlated with higher tumorigenicity in mice. Furthermore, when breast cancer cell lines were treated with IGFBP7, only the TNBC cell lines were growth inhibited. Treatment of NOD/SCID mice harboring xenografts of TNBC cells with IGFBP7 systemically every 3-4 days inhibited tumorigenesis, with associated anti-angiogenic effects, together with increased apoptosis. Upon examining the mechanism of IGFBP7-mediated growth inhibition in TNBC cells, we found that cells not only were arrested in G1 phase of the cell cycle but also underwent senescence as a result of treatment with IGFBP7. Interestingly, IGFBP7 treatment was also associated with strong activation of the stress-associated p38 MAPK pathway, together with upregulation of p53 and the cyclin-dependent protein kinase (CDK) inhibitor, p21(cip1). Prolonged treatment of cells with IGFBP7 resulted in increased cell death, marked by an increase in apoptotic cells and associated cleaved PARP. This is the first study showing that exogenous IGFBP7 inhibits TNBC cell growth both in vitro and in vivo. Taken together, these results suggest IGFBP7 treatment might have therapeutic potential for TNBC.

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Metadata

Authors
Benatar, T., Yang, W., Amemiya, Y., Evdokimova, V., Kahn, H., Holloway, C., & Seth, A.
Affiliations
  • Sunnybrook Research Institute (CA)
  • Institute of Protein Research (RU)
  • Sunnybrook Health Science Centre (CA)
Corresponding author
Seth, Arun
ORCID
Venue
Breast Cancer Research and Treatment
Publisher
Springer Science and Business Media LLC
Published
2011-10-14
Volume
133
Issue
2
Pages
563-573
ISSN
  • 0167-6806 (ISSN-L)
  • 1573-7217
DOI
10.1007/s10549-011-1816-4
OpenAlex
W1993584752
Cited by
89
References
5
Citations by year
2026: 5 · 2025: 3 · 2024: 7 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 10 · 2017: 5 · 2016: 5 · 2015: 5 · 2014: 12 · 2013: 6 · 2012: 4
FWCI
4.80
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Breast Cancer Research and Treatment (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (97996_1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
Keywords
IGFBP7, triple-negative breast cancer, tumor suppressor, cellular senescence, apoptosis, p38 MAPK pathway, p53, p21, G1 cell cycle arrest, angiogenesis inhibition, xenograft tumor growth inhibition, therapeutic target
MeSH terms
Animals, Breast Neoplasms, Female, Humans, Receptors, Estrogen, Receptors, Progesterone, Signal Transduction, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, Apoptosis, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Insulin-Like Growth Factor Binding Proteins, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Cell Cycle Checkpoints

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