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Cited by 162Growth Hormone and Insulin-like Growth FactorsMetabolism, Diabetes, and CancerFibroblast Growth Factor Research

Down-regulation of type I insulin-like growth factor receptor increases sensitivity of breast cancer cells to insulin

Zhang, Hua, Pelzer, Alissa M., Kiang, David T., Yee, Douglas·2007·Cancer Research
DOI 10.1158/0008-5472.can-06-1712
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Abstract

The type I insulin-like growth factor receptor (IGF1R) and insulin receptor (IR) are structurally and functionally related heterotetrameric receptors. Activation of IGF1R has been shown to regulate breast cancer cell biology, and it has become an attractive therapeutic target. Most strategies have focused on targeting IGF1R alone without affecting IR levels given the known physiologic functions of IR. Human breast cancer cell lines and tissues revealed mRNA expression of both IGF1R and IR. Because alphabeta chains of IGF1R and IR form hybrid receptors, we hypothesized that agents solely targeting IGF1R may affect tumor biology mediated by IGF1R/IR hybrids and IR. We used small interfering RNA (siRNA) technology to specifically down-regulate IGF1R by 60% to 80% in the MDA-435/LCC6 cell line, which was sufficient to diminish activation of IGF1R by IGF-I. IGF1R down-regulation by siRNA did not affect IR levels but, interestingly, sensitized cells to insulin activation of downstream signaling pathways in several breast cancer cell lines. IGF1R siRNA treatment diminished hybrid receptor formation, suggesting that specific down-regulation of IGF1R resulted in enhanced holo-IR formation. In addition, IGF1R down-regulation increased insulin binding consistent with the formation of an increased number of holo-IR on the cell surface. Accordingly, insulin-stimulated glucose uptake was enhanced on IGF1R down-regulation. In conclusion, our data suggest that specific siRNA targeting of IGF1R alone in breast cancer increases insulin sensitivity. Because IR also activates signaling pathways similar to IGF1R in breast cancer cells, agents targeting both receptors may be necessary to disrupt the malignant phenotype regulated by this growth factor system.

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Crossref · 10.1158/0008-5472.can-06-1712

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  • Because most glucose uptake in cancer cells is constitutively high and independent of insulin binding to its receptor, the effects of insulin receptor activation on neoplastic cells may relate more to cell survival and mitogenesis than to enhanced glucose uptake.

    “Because most glucose uptake in cancer cells is constitutively high and independent of insulin binding to its receptor (51), the effects of insulin receptor activation on neoplastic cells may relate more to cell survival and mitogenesis than to enhanced glucose uptake.”

    From Diabetes and Cancer (2010) · cites this paper as [51]

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Authors
Zhang, H., Pelzer, A. M., Kiang, D. T., & Yee, D.
Affiliations
University of Minnesota (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2007-01-01
Volume
67
Issue
1
Pages
391-397
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-06-1712
OpenAlex
W2106213925
Cited by
162
References
35
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 5 · 2018: 9 · 2017: 7 · 2016: 7 · 2015: 10 · 2014: 15 · 2013: 7 · 2012: 12
FWCI
10.47
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (P30 CA77398, R01CA74285, R01CA074285)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
Keywords
IGF-1 receptor, insulin receptor, breast cancer, insulin sensitivity, hybrid receptors, insulin-stimulated glucose uptake, insulin receptor signaling, siRNA knockdown, insulin-like growth factor I
MeSH terms
Breast Neoplasms, Glucose, Humans, Insulin, Insulin-Like Growth Factor I, Receptor, Insulin, RNA, Messenger, Transfection, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Receptor, IGF Type 1, Protein Isoforms, RNA, Small Interfering, Cell Line, Tumor

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