Activator protein-2 overexpression accounts for increased insulin receptor expression in human breast cancer
Abstract
Various studies have shown that the insulin receptor (IR) is increased in most human breast cancers, and both ligand-dependent malignant transformation and increased cell growth occur in cultured breast cells overexpressing the IR. However, although numerous in vivo and in vitro observations have indicated an important contributory role for the IR in breast cancer cell biology, the molecular mechanisms accounting for increased IR expression in breast tumors have not previously been elucidated. Herein, we did immunoblot analyses of nuclear protein from cultured breast cancer cells and normal and tumoral tissues from breast cancer patients combined with promoter studies by using a series of human wild-type and mutant IR promoter constructs. We provide evidence that IR overexpression in breast cancer is dependent on the assembly of a transcriptionally active multiprotein-DNA complex, which includes the high-mobility group A1 (HMGA1) protein, the developmentally regulated activator protein-2 (AP-2) transcription factor and the ubiquitously expressed transcription factor Sp1. In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression. However, AP-2 DNA-binding activity was undetectable with the IR gene promoter, suggesting that transactivation of this gene by AP-2 might occur indirectly through physical and functional cooperation with HMGA1 and Sp1. Our findings support this hypothesis and suggest that in affected individuals, hyperactivation of the AP-2 gene through the overexpression of IR may play a key role in breast carcinogenesis.
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HMGA1 is a crucial regulator of INSR gene transcription, directing assembly of a transcriptionally active multiprotein-DNA complex on the INSR gene promoter.
“The high-mobility group A1 protein (HMGA1) is as a crucial regulator of INSR gene transcription, which directs the assembly of a transcriptionally active multiprotein-DNA complex on the INSR gene promoter [169,170].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [169]
Physical and functional cooperation between transcription factor AP2 and HMGA1 is a fundamental prerequisite for INSR overexpression in neoplastic breast tissues.
“As demonstrated by our group [169], the physical and functional cooperation between the transcription factor AP2 and HMGA1 is a fundamental prerequisite for INSR overexpression in neoplastic breast tissues.”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [169]
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“In these circumstances, INSR can exert its oncogenic potential, by directly affecting cell metabolism and/or by synergizing with other oncogenes, with adverse impact on tumor growth and differentiation [169].”
BackgroundInfluentialSelf-citationHigh Mobility Group A (HMGA) proteins: Molecular instigators of breast cancer onset and progression
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- Authors
- Paonessa, F., Foti, D., Costa, V., Chiefari, E., Brunetti, G., Leone, F., Luciano, F., Wu, F., Lee, A. S., Gulletta, E., Fusco, A., & Brunetti, A.
- Affiliations
- Magna Graecia University (IT)
- University of Milan (IT)
- Azienda Ospedaliera Pugliese Ciaccio (IT)
- University of Southern California (US)
- CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT)
- ORCID
- Venue
- Cancer Research
- Published
- 2006-05-15
- Volume
- 66
- Issue
- 10
- Pages
- 5085-5093
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2141810686
- Cited by
- 52
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 6
- FWCI
- 2.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- insulin receptor, breast cancer, activator protein-2, HMGA1, Sp1, transcriptional regulation, transcription factor complex, mammary carcinogenesis, gene overexpression
- MeSH terms
- Breast Neoplasms, DNA, Neoplasm, HeLa Cells, Humans, Promoter Regions, Genetic, Receptor, Insulin, Gene Expression Regulation, Neoplastic, Sp1 Transcription Factor, HMGA1a Protein, Cell Line, Tumor, Transcription Factor AP-2
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