New Insights into the Role of the Insulin-Like Growth Factors in Breast Cancer
Main Article Content
Abstract
The insulin-like growth factor-1 hormonal axis has emerged in recent years as a promising therapeutic target in oncology. Empirical support to this view was provided by pre-clinical studies showing that insulin-like growth factor-1 receptor expression and activation constitute fundamental prerequisites for breast cancer development. Unfortunately, the vast majority of phase III clinical trials using monoclonal antibodies against the receptor have been disappointing. As a result of these negative outcomes there is an urgent need to identify predictive biomarkers that may identify potential responders. The present review article is aimed at providing an overview of the role of the insulin-like growth factor-1 axis in breast cancer. Circulating insulin-like growth factor-1 constitutes a risk factor for a number of malignancies, including breast cancer, and various members of the insulin-like growth factor-1 system are produced by the tumoral cells or by stromal cells. In addition, we provide evidence that the mechanism of action of insulin-like growth factor-1 involves interactions with the estrogen receptor as well as with the breast cancer gene-1. Finally, lifestyle factors that are related to insulin-like growth factor-1, such as obesity, have been suggested to have an effect on breast cancer.
Keywords:
insulin-like growth factor-1 (IGF1), IGF1 receptor, breast cancer, BRCA1, estrogen receptor
Article Details
How to Cite
WERNER, Haim.
New Insights into the Role of the Insulin-Like Growth Factors in Breast Cancer.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3634>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3634.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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11. Werner H, Sarfstein R. Transcriptional and epigenetic control of IGF1R gene expression: implications in metabolism and cancer. Growth Hormone IGF Res. 2014;24:112-118.
12. LeRoith D. Clinical relevance of systemic and local IGF-I: lessons from animal models. Pediatr Endocrinol Rev. 2008;5(Suppl 2):739-743.
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19. Holly J, Perks C. The role of insulin-like growth factor binding proteins. Neuroendocrinology. 2006;83:154-160.
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26. Cannata D, Lann D, Wu Y, et al. Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology. 2010;151:5751-5761.
27. de Ostrovich KK, Lambertz I, Colby JK, et al. Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo. Am J Pathol. 2008;173:824-834.
28. Baserga R, Resnicoff M, Dews M. The IGF-1 receptor and cancer. Endocrine. 1997;7:99-102.
29. O'Connor R, Kauffmann-Zeh A, Liu Y, et al. Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 1997;17:427-435.
30. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev Cancer. 2012;12:159-169.
31. Nam SY, Lee EJ, Kim KR, et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metaab Disord. 1997;21:355-359.
32. Gallagher EJ, LeRoith D. Obesity and cancer. Cancer Metastasis Rev. 2022;41:463-364.
33. Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13(12):e537-544.
34. Koobotse M, Holly J, Perks C. Elucidating the novel BRCA1 function as a non-genomic metabolic restraint in ER-positive breast cancer cell lines. Oncotarget. 2018;9:33562-33576.
35. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66-71.
36. Werner H. BRCA1: an endocrine and metabolic regulator. Front Endocrinol. 2022;13:844575.
37. Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266:120-122.
38. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692-695.
39. Abramovitch S, Glaser T, Ouchi T, Werner H. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene. FEBS Lett. 2003;541:149-154.
40. Maor SB, Abramovitch S, Erdos MR, et al. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Gen Metab. 2000;69:130-136.
41. Shukla V, Coumoul X, Cao L, et al. Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. Cancer Res. 2006;66:7151-7157.
42. Maor S, Yosepovich A, Papa MZ, et al. Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett. 2007;257:236-243.
43. Hudelist G, Wagner T, Rosner M, et al. Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations. Endocrine Related Cancer. 2007;14:1053-1062.
44. Maor S, Papa MZ, Yarden RI, et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res. 2007;39:179-185.
45. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001;1:467-475.
46. Massague J. G1 cell-cycle control and cancer. Nature. 2004;432:298-306.
47. Mawson A, Lai A, Carroll JS, et al. Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol Cell Endocrinol. 2005;229:161-173.
48. Maor S, Mayer D, Yarden RI, et al. Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol. 2006;191:605-612.
49. Hankinson SE, Willett WC, Michaud DS, et al. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1999;91:629-634.
50. Carver KC, Schuler LA. Prolactin does not require insulin-like growth factor intermediates but synergizes with insulin-like growth factor I in human breast cancer cells. Mol Cancer Res. 2008;6:634-643.
51. Yuen JS, Macaulay VM. Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Exp Opinion Ther Targets. 2008;12:589-603.
52. Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Exp Opinion Ther Targets. 2009;13:1179-1192.
53. Baserga R. The decline and fall of the IGF-I receptor. J Cell Physiol. 2013;28:675-679.
54. Cohen-Sinai T, Cohen Z, Werner H, Berger R. Identification of BRCA1 as a potential biomarker for insulin-like growth factor-1 receptor targeted therapy in breast cancer. Front Endocrinol (Lausanne). 2017;8:148.
55. Pavlicek A, Lira ME, Lee NV, et al. Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871). Mol Cancer Ther. 2013;12:2929-2939.
56. Farabaugh S, Boone D, Lee A. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation. Front. Endocrinol (Lausanne). 2015;6:59.
57. Yerushalmi R, Gelmon KA, Leung S, et al. Insulin-like growth factor receptor (IGF-IR) in breast subtypes. Breast Cancer Res. Treat. 2012;132:131-142.
58. King H, Aleksic T, Haluska P, Macaulay VM. Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer Treat Rev. 2014;40:1096-1105.
2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359-386.
3. Torre LA, Islami F, Siegel RL, et al. Global Cancer in Women: Burden and Trends. Cancer Epidemiol Biomarkers Prev. 2017;26:444-457.
4. Osher E, Macaulay VM. Therapeutic targeting of the IGF axis. Cells. 2019;8:E895.
5. Crudden C, Girnita A, Girnita L. Targeting the IGF-1R: the tale of the tortoise and the hare. Front Endocrinol (Lausanne). 2015;6:64.
6. Scotlandi K, Picci P. Targeting insulin-like growth factor 1 receptor in sarcomas. Curr Opinion Oncol. 2008;20:419-427.
7. Bentov I, Werner H. IGF, IGF receptor and overgrowth syndromes. Pediatr Endocrinol Rev. 2004;1:352-360.
8. Salmon WD, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med. 1957;49:825-836.
9. Rosenfeld RG. Insulin-like growth factors and the basis of growth. New England J Med. 2003;349:2184-2186.
10. De Meyts P. Insulin/receptor binding: the last piece of the puzzle? What recent progress on the structure of the insulin/receptor complex tells us (or not) about negative cooperativity and activation. Bioessays. 2015;37:389-397.
11. Werner H, Sarfstein R. Transcriptional and epigenetic control of IGF1R gene expression: implications in metabolism and cancer. Growth Hormone IGF Res. 2014;24:112-118.
12. LeRoith D. Clinical relevance of systemic and local IGF-I: lessons from animal models. Pediatr Endocrinol Rev. 2008;5(Suppl 2):739-743.
13. Baker J, Liu J-P, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell. 1993;75:73-82.
14. Belfiore A, Malaguarnera R. The insulin receptor and cancer. Endocrine Related Cancer. 2011;18:R125-147.
15. Baserga R, Peruzzi F, Reiss K. The IGF-1 receptor in cancer biology. Int J Cancer. 2003;107:873-877.
16. Werner H, Laron Z. Role of the GH-IGF1 system in progression of cancer. Mol Cell Endocrinol. 2020;518:111003.
17. Sarfstein R, Maor S, Reizner N, et al. Transcriptional regulation of the insulin-like growth factor-1 receptor in breast cancer. Mol Cell Endocrinol. 2006;252:241-246.
18. LeRoith D, Helman LJ. The new kid on the block(ade) of the IGF-1 receptor. Cancer Cell. 2004;5:403.
19. Holly J, Perks C. The role of insulin-like growth factor binding proteins. Neuroendocrinology. 2006;83:154-160.
20. Bach L. Insulin-Like Growth Factor Binding Proteins--an Update. Pediatr Endocrinol Rev. 2015;13:521-530.
21. McGuire W, Jackson JG, Figueroa JA, et al. Regulation of IGFBP expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action. J Natl Cancer Inst. 1992;84:1336-1341.
22. Shi R, Yu H, McLarty J, Glass J. IGF-I and breast cancer: a meta analysis. Int J Cancer. 2004;111:418-423.
23. Renehan AG, Zwahlen M, Minder C, et al. Insulin-like growth factor-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet. 2004;363:1346-1353.
24. Hankinson SE, Willett WC, Colditz GA, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998;351:1393-1396.
25. Vella V, De Francesco EM, Lappano R, et al. Microenvironmental determinants of breast cancer metastasis: focus on the crucial interplay between estrogen and insulin/insulin-like growth factor signaling. Front Cell Dev Biol. 2020;8:608412.
26. Cannata D, Lann D, Wu Y, et al. Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology. 2010;151:5751-5761.
27. de Ostrovich KK, Lambertz I, Colby JK, et al. Paracrine overexpression of insulin-like growth factor-1 enhances mammary tumorigenesis in vivo. Am J Pathol. 2008;173:824-834.
28. Baserga R, Resnicoff M, Dews M. The IGF-1 receptor and cancer. Endocrine. 1997;7:99-102.
29. O'Connor R, Kauffmann-Zeh A, Liu Y, et al. Identification of domains of the insulin-like growth factor I receptor that are required for protection from apoptosis. Mol Cell Biol. 1997;17:427-435.
30. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nature Rev Cancer. 2012;12:159-169.
31. Nam SY, Lee EJ, Kim KR, et al. Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metaab Disord. 1997;21:355-359.
32. Gallagher EJ, LeRoith D. Obesity and cancer. Cancer Metastasis Rev. 2022;41:463-364.
33. Werner H, Bruchim I. IGF-1 and BRCA1 signalling pathways in familial cancer. Lancet Oncol. 2012;13(12):e537-544.
34. Koobotse M, Holly J, Perks C. Elucidating the novel BRCA1 function as a non-genomic metabolic restraint in ER-positive breast cancer cell lines. Oncotarget. 2018;9:33562-33576.
35. Miki Y, Swensen J, Shattuck-Eidens D, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66-71.
36. Werner H. BRCA1: an endocrine and metabolic regulator. Front Endocrinol. 2022;13:844575.
37. Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994;266:120-122.
38. Ford D, Easton DF, Bishop DT, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692-695.
39. Abramovitch S, Glaser T, Ouchi T, Werner H. BRCA1-Sp1 interactions in transcriptional regulation of the IGF-IR gene. FEBS Lett. 2003;541:149-154.
40. Maor SB, Abramovitch S, Erdos MR, et al. BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Mol Gen Metab. 2000;69:130-136.
41. Shukla V, Coumoul X, Cao L, et al. Absence of the full-length breast cancer-associated gene-1 leads to increased expression of insulin-like growth factor signaling axis members. Cancer Res. 2006;66:7151-7157.
42. Maor S, Yosepovich A, Papa MZ, et al. Elevated insulin-like growth factor-I receptor (IGF-IR) levels in primary breast tumors associated with BRCA1 mutations. Cancer Lett. 2007;257:236-243.
43. Hudelist G, Wagner T, Rosner M, et al. Intratumoral IGF-I protein expression is selectively upregulated in breast cancer patients with BRCA1/2 mutations. Endocrine Related Cancer. 2007;14:1053-1062.
44. Maor S, Papa MZ, Yarden RI, et al. Insulin-like growth factor-I controls BRCA1 gene expression through activation of transcription factor Sp1. Horm Metab Res. 2007;39:179-185.
45. Hennighausen L, Robinson GW. Signaling pathways in mammary gland development. Dev Cell. 2001;1:467-475.
46. Massague J. G1 cell-cycle control and cancer. Nature. 2004;432:298-306.
47. Mawson A, Lai A, Carroll JS, et al. Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol Cell Endocrinol. 2005;229:161-173.
48. Maor S, Mayer D, Yarden RI, et al. Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol. 2006;191:605-612.
49. Hankinson SE, Willett WC, Michaud DS, et al. Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1999;91:629-634.
50. Carver KC, Schuler LA. Prolactin does not require insulin-like growth factor intermediates but synergizes with insulin-like growth factor I in human breast cancer cells. Mol Cancer Res. 2008;6:634-643.
51. Yuen JS, Macaulay VM. Targeting the type 1 insulin-like growth factor receptor as a treatment for cancer. Exp Opinion Ther Targets. 2008;12:589-603.
52. Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Exp Opinion Ther Targets. 2009;13:1179-1192.
53. Baserga R. The decline and fall of the IGF-I receptor. J Cell Physiol. 2013;28:675-679.
54. Cohen-Sinai T, Cohen Z, Werner H, Berger R. Identification of BRCA1 as a potential biomarker for insulin-like growth factor-1 receptor targeted therapy in breast cancer. Front Endocrinol (Lausanne). 2017;8:148.
55. Pavlicek A, Lira ME, Lee NV, et al. Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871). Mol Cancer Ther. 2013;12:2929-2939.
56. Farabaugh S, Boone D, Lee A. Role of IGF1R in breast cancer subtypes, stemness, and lineage differentiation. Front. Endocrinol (Lausanne). 2015;6:59.
57. Yerushalmi R, Gelmon KA, Leung S, et al. Insulin-like growth factor receptor (IGF-IR) in breast subtypes. Breast Cancer Res. Treat. 2012;132:131-142.
58. King H, Aleksic T, Haluska P, Macaulay VM. Can we unlock the potential of IGF-1R inhibition in cancer therapy? Cancer Treat Rev. 2014;40:1096-1105.