Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer
Abstract
:1. Introduction
2. Molecular Characteristics and Functional Roles of IGF-1 Isoforms in Health and Disease
3. The Role of IGF-1, Its Isoforms, and IGF-1R in Breast Cancer
3.1. IGF-1 in Breast Cancer
3.2. IGF-1 Isoforms and Receptor Interactions in Breast Cancer
Study (Reference) | Research Focus | Key Findings | Clinical/Scientific Impact |
---|---|---|---|
Mauro De Santi et al., 2023 [78] | Association between IGF-1 levels, MetS, and insulin resistance in BC survivors | - Lower circulating IGF-1 levels in BC survivors with MetS compared to those without MetS - Interaction between HDL-C, glycemia, and IGF-1 levels, especially in subjects without MetS | - Highlights the impact of metabolic syndrome and insulin resistance on IGF-1 levels in BC survivors - Potential lifestyle interventions to modulate IGF-1 concentrations |
Heba Mohammed Arafat et al., 2023 [76] | Investigate the relationship between IGF-1 and IGFBP-3 levels and BC risk among women in Gaza | - Age, lower physical activity, increased FBG, and IGF-1 levels were associated with an increased BC risk | - Identifies key risk factors for BC specific to the Gaza Strip population |
Heidari S. et al., 2022 [79] | IGF-1 expression in serum and peritoneal fluid of BC patients | - Increased IGF-1 expression in the serum and peritoneal fluid of BC patients compared to controls | - Supports the role of IGF-1 in BC progression and metastasis |
Lee et al., 2022 [13] | Prognostic value of IGF-1R across BC subtypes | IGF-1R expression was associated with poor survival across all BC subtypes and more pronounced in certain subtypes | - Highlights the functional significance of IGF-1R phosphorylation in BC prognosis |
Biello et al., 2021 [16] | IGF Expression in relation to BC characteristics | - Higher IGF expression was associated with worse prognostic features in BC | - Provides insights into the association between IGF expression levels and the clinical characteristics of BC |
Kamdje et al., 2021 [80] | IGF-1 and mammary tumor microenvironment | - Role of IGF-1 in regulating mammary tumor microenvironment; implications for tumor growth and metastasis | - Explores the influence of IGF-1 on tumor microenvironment dynamics and therapeutic strategies targeting IGF-1 |
Jennifer Tsui et al., 2021 [81] | IGF-1 and chemotherapy response in TNBC | - Study evaluating the role of IGF-1 in chemotherapy response and prognosis in TNBC | - Explores therapeutic implications of IGF-1 pathway inhibition in TNBC |
Murphy et al. 2020 [65] | Mendelian randomization of circulating IGF-1 and BC risk | - Higher circulating IGF-1 levels associated with increased BC risk; a causal relationship was suggested | - Supports IGF-1 as a potential target for BC prevention strategies |
Y Zhu et al., 2020 [77] | Association of circulating IGF-1 with BC mortality | - Inverse association between high circulating IGF-1 and all-cause mortality in BC patients | - Suggests a potential protective role of circulating IGF-1 in BC outcomes, especially in specific patient subgroups |
Yiwei Tong et al., 2020 [82] | Evaluate the prognostic value of IGF-1 and metabolic abnormalities in HER2+ BC patients | - High IGF-1 levels are more common in pre/perimenopausal women and those with high IGFBP-3 - IGF-1 level was not associated with recurrence-free survival (RFS) in the whole population | - Identifies a subset of patients with distinct prognostic profiles based on IGF-1 levels - IGF-1 levels alone are not sufficient as a prognostic marker for RFS |
Yujing Zhou et al., 2020 [83] | IGF-1 and estrogen (ERβ) in BC progression | - IGF-1 stimulates ERβ and aromatase overexpression in BC cells, promoting disease progression | - Highlights IGF-1′s role in promoting estrogen-driven pathways in BC |
Gui-Ping Xu et al., 2018 [84] | Investigate the association between the rs1520220 polymorphism in the IGF1 gene and cancer susceptibility | - No overall positive association between rs1520220 and cancer risk | - Provides evidence that rs1520220 may not be a universal marker for cancer risk |
H Li et al., 2016 [85] | Genetic polymorphisms in IGF-1 and BC risk | - Association between IGF-1 gene polymorphisms and BC risk; ethnic and subtype-specific differences | - Highlights genetic variations in IGF-1 and their impact on BC susceptibility across different populations |
O’Flanagan et al., 2016 [86] | IGF-1R signaling and DNA damage response | - IGF-1R signaling sensitizes BC cells to cisplatin-induced DNA damage via ATM/ATR pathways, implicating IGF-1R in DNA repair mechanisms | - Highlights IGF-1R as a potential target for enhancing the DNA damage response in BC therapy |
Christopoulos et al., 2015 [15] | Prognostic impact of IGF-1R expression among BC subtypes | - IGF-1R expression varies across BC subtypes; associated with a better BCSS in Luminal B but a worse outcome in the HER2-enriched subtype | - Highlights subtype-specific prognostic implications of IGF-1R expression, with potential for targeted therapies |
Yerushalmi et al., 2012 [87] | Differential expression of tissue IGF-1 and BC subtypes | - Tissue IGF-1 levels were associated with a better prognosis in ER+ BC, in a conflicting role compared to serum IGF-1 levels | - Emphasizes the discrepancy between circulating and tissue-specific IGF-1 levels in BC prognosis |
Litzenburger et al., 2011 [88] | IGF-1R inhibitors in BC cell lines | - Effective inhibition of IGF-1R with BMS-754807 in ΤΝBC cell lines, reversing IGF-1R-activated gene expression signatures | - Demonstrates the potential efficacy of IGF-1R inhibitors in ER-negative and HER2− BCs |
Aleksic et al., 2010 [45] | IGF-1R nuclear translocation in BC | - Nuclear localization of IGF-1R was associated with aggressive tumor behavior and poor prognosis in BC | - Investigates the role of IGF-1R nuclear translocation as a prognostic marker and potential therapeutic target |
Runhua Shi et al., 2004 [89] | Evaluate the association of IGF-1 and IGFBP-3 levels with BC risk through a meta-analysis | - Circulating levels of IGF-1 were significantly higher in premenopausal BC patients | - Supports the association between high IGF-1 levels and increased BC risk in premenopausal women. |
Type of Evidence | Cell Lines | IGF-1 or IGF-1 Isoform of Interest | Method | Results | References |
---|---|---|---|---|---|
In vitro | MCF-7 | Ec peptide | MTT assay/Trypan Blue | hEc in low doses stimulated the proliferation of wt cells | [59] |
rhIGF-1 | Exogenous administration of human mature IGF-1 (rhIGF-1) in monolayer cultures stimulated the growth/metabolic activity of wt cells | ||||
Ec peptide | Wound healing/Scratch assay | MCF-7Ec cells have increased motility/migration capability compared to wt cells | |||
Ec peptide | qPCR | An upregulation of Cdh-11, an indicative marker of EMT in MCF-7Ec cells, was detected | |||
MDA-MB-231 | Ec peptide | MTT assay/Trypan Blue | hEc did not stimulate the proliferation of wt cells | [90] | |
rhIGF-1 | Exogenous administration of rhIGF-1 in monolayer cultures stimulated the growth/metabolic activity of wt cells | ||||
rhIGF-1 | Wound healing/Scratch assay | IGF-1 increased MDA-MB-231 cell migration approximately tenfold with half maximal stimulation at a concentration of 12 ng/ml | |||
In vivo | MCF-7 | IGF-1 | Mouse xenograft experiments | MCF-7 cells stably overexpressing IGF-1 induce significantly higher tumor volumes compared with control or mock cells | [15] |
Increased activation of the PI3K/AKT/mTOR pathway facilitated BCSC maintenance and increased their EMT phenotype | |||||
Immortalized human mammary epithelial cells | IGF-1R | Mouse xenografts experiments | Overexpression of IGF-1R caused cells to undergo EMT which was associated with dramatically increased migration and invasion | [91] | |
MDA-MB-231 | IGF-1/IGF-1R | TNBC patients | IGF-1 and IGF-1R overexpression were associated with an increased incidence of metastases and decreased survival | [92] |
3.3. The Role of IGF-1 Signaling in Breast Cancer
4. The Role of IGF-1 in Breast Cancer: Mechanisms of Proliferation, Angiogenesis, Metastasis, and Resistance
4.1. Cell Proliferation and Survival
4.2. Angiogenesis and Metastasis
4.3. Resistance and Apoptosis
5. Clinical Implication and Therapeutic Potential
5.1. Therapeutic Targeting of IGF-1 and Its Isoforms
5.2. Monoclonal Antibodies and Small Molecule Inhibitors in IGF-1R Targeting
5.3. Emerging Therapies and Novel Approaches in IGF-1 and Its Receptor Inhibition
6. Future Directions in Research
7. Discussion
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Isoform | Structure | Generation Mechanism | Alternative Splicing | Functional Characteristics and Differences | Primary Signaling Pathways | Predominant Tissues |
---|---|---|---|---|---|---|
IGF-1Ea | Exons 1, 2, 3, 4, 5 | Splicing of exons 1–5 from the igf-1 gene | Modulates exon 5 inclusion/exclusion | - Similar to hepatic IGF-1, involved in systemic growth regulation - Promotes cell proliferation, survival, and metabolic functions - Interacts with IGFBPs to regulate bioavailability and activity | - PI3K/Akt, - MAPK (ERK1/2), - JAK/STAT - IGF-1R - IGFBPs - The specific roles and predominant tissues of each IGF-1 isoform can vary depending on developmental stage, physiological conditions, and species-specific differences. | - Liver, muscle, bone, brain, and adipose tissue |
IGF-1Eb | Exons 1, 2, 3, 4, 6 | Splicing of exons 1–4, 6 from the igf-1 gene | Excludes exon 5 | - Predominantly expressed in liver, role in growth regulation - Specific role in growth modulation, potential interactions with IGFBPs | - Liver, muscle, and testes - Other Tissues: Present but with less clear predominant roles compared to IGF-1a and IGF-1c | |
IGF-1Ec | Exons 1, 2, 3, 5, 6 | Splicing of exons 1, 2, 3, 5, 6 from the igf-1 gene | Excludes exon 4 | - Response to mechanical stress in tissues - Enhances cell migration, tissue remodeling, and repair processes - Cleaved COO-terminal peptide (PEc) induces cellular proliferation and epithelial to mesenchymal transition (metastasis in prostate cancer) | - Muscle, heart, bone, and tendons |
Patient Group | IGF-1 Expression (%) | Estrogen Receptor Status |
---|---|---|
ER+ (Positive) | 60% | IGF-1R is often associated with ER+ BC |
Triple-Negative (TNBC) | 20% | IGF-1R expression tends to be lower in TNBC compared to ER+ subtypes |
Tumor Stage | ||
Early (T1–T2) | 35% | Higher IGF-1 expression correlates with more advanced BC stages (T3–T4) |
Advanced (T3–T4) | 65% | |
Lymph Node Status | ||
Metastasis Present | 60% | IGF-1 expression is higher in BC patients with lymph node metastasis |
No Metastasis | 40% | Lower IGF-1 expression is observed in BC patients without lymph node involvement |
BC Subtype | Percentage of IGF-1R Expression | Key Findings |
---|---|---|
Luminal A | ~52% | IGF-1R expression does not affect breast cancer specific survival. |
Luminal B | ~57.5% | Higher total IGF-1R levels correlate with a better prognosis. |
HR+/ERBB2+ | ~10–20% | Active phosphorylated IGF-1R/IR does not correlate with prognosis in trastuzumab-treated ERBB2+ tumors. |
TNBC | ~22–46% | IGF-1R expression correlates with shorter survival. TNBCs are responsive to IGF-1 signaling promoting proliferation and survival. |
Target Component of the IGF-1 System | Details of Agent | BC Subtype | Phase of Development | Status | Combination Therapy | References |
---|---|---|---|---|---|---|
GH-RH | Antagonists JV-1-36 or JMR-132 | TNBC | II | Completed | Docetaxel | [143] |
Somatostatin analog: Octreotide | Stage I, II, III BC HER2+ metastatic BC | ΙΙ | Completed Ongoing | Tamoxifen, ovariectomy | [152] | |
Somatostatin analog: Pasireotide | Stage I, II, III BC | I | Ongoing | - | [153] | |
IGF-1 | Neutralizing monoclinic antibody: MEDI-573 | Hormone-sensitive, HER2− metastatic BC | II | Ongoing | Aromatase inhibitor | [154] |
mAb: BI 836845 | Hormone-sensitive, HER2− metastatic BC | I | Ongoing | Everolimus, Exemestane | [155] | |
IGF-1R | mAb: CP-751.871 | Postmenopausal subjects with advanced HR+ BC | II | Terminated | Exemestane, fulvestrant | [156] |
mAb: AMG-479 | Postmenopausal subjects with locally advanced or metastatic HR+ BC | II | Completed | Exemestane, fulvestrant | [157] | |
mAb: IMC-A12 | HER2 positive advanced BC resistant to transtuzumab and/or anthracyclines | II | Ongoing | Capecitabine, Lapatinib | [158] | |
mAb: MK-0646 | ER+/HER2-BC TNBC | II | Completed | Ridaforolimus, exemestane | [159] | |
IGF-1R RTKI | OSI-906 | Hormone-sensitive metastatic BC | II | Terminated | Erlotinib, Letrozole, Goserelin | [160] |
BMS-754807 | HER2+ advanced or metastatic BC HR+, HER2−, resistant to non-steroidal aromatase inhibitors | II | Completed | Trastuzumab, Letrozole | [161] |
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Kotsifaki, A.; Maroulaki, S.; Karalexis, E.; Stathaki, M.; Armakolas, A. Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer. Int. J. Mol. Sci. 2024, 25, 9302. https://doi.org/10.3390/ijms25179302
Kotsifaki A, Maroulaki S, Karalexis E, Stathaki M, Armakolas A. Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer. International Journal of Molecular Sciences. 2024; 25(17):9302. https://doi.org/10.3390/ijms25179302
Chicago/Turabian StyleKotsifaki, Amalia, Sousanna Maroulaki, Efthymios Karalexis, Martha Stathaki, and Athanasios Armakolas. 2024. "Decoding the Role of Insulin-like Growth Factor 1 and Its Isoforms in Breast Cancer" International Journal of Molecular Sciences 25, no. 17: 9302. https://doi.org/10.3390/ijms25179302