Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 1/2015

Open Access 01-12-2015 | Research article

Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/+WAPCre mouse model

Authors: Bas ter Braak, Christine Siezen, Ewoud N Speksnijder, Esmee Koedoot, Harry van Steeg, Daniela CF Salvatori, Bob van de Water, Jan Willem van der Laan

Published in: Breast Cancer Research | Issue 1/2015

Login to get access

Abstract

Introduction

Insulin analogues are structurally modified molecules with altered pharmaco-kinetic and -dynamic properties compared to regular human insulin used by diabetic patients. While these compounds are tested for undesired mitogenic effects, an epidemiological discussion is ongoing regarding an association between insulin analogue therapy and increased cancer incidence, including breast cancer. Standard in vivo rodent carcinogenesis assays do not pick up this possible increased carcinogenic potential.

Methods

Here we studied the role of insulin analogues in breast cancer development. For this we used the human relevant mammary gland specific p53R270H/+WAPCre mouse model. Animals received life long repeated treatment with four different insulin (−like) molecules: normal insulin, insulin glargine, insulin X10 (AspB10) or insulin-like growth factor 1 (IGF1).

Results

Insulin-like molecules with strong mitogenic signaling, insulin X10 and IGF1, significantly decreased the time for tumor development. Yet, insulin glargine and normal insulin, did not significantly decrease the latency time for (mammary gland) tumor development. The majority of tumors had an epithelial to mesenchymal transition phenotype (EMT), irrespective of treatment condition. Enhanced extracellular signaling related kinase (Erk) or serine/threonine kinase (Akt) mitogenic signaling was in particular present in tumors from the insulin X10 and IGF1 treatment groups.

Conclusions

These data indicate that insulin-like molecules with enhanced mitogenic signaling increase the risk of breast cancer development. Moreover, the use of a tissue specific cancer model, like the p53R270H/+WAPCre mouse model, is relevant to assess the intrinsic pro-carcinogenic potential of mitogenic and non-mitogenic biologicals such as insulin analogues.
Appendix
Available only for authorised users
Literature
1.
Dideriksen LH, Jorgensen LN, Drejer K. Carcinogenic effect of female rats after 12 months administration of the insulin analogue B10Asp [abstact]. Diabetes. 1992;41 Suppl 1:143A.
2.
Hansen BF, Danielsen GM, Drejer K, Sorensen AR, Wiberg FC, Klein HH, et al. Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J. 1996;315:271–9.CrossRefPubMedPubMedCentral
3.
Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, et al. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49:999–1005.CrossRefPubMed
4.
Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev. 2009;25:41–9.CrossRefPubMed
5.
6.
Tamimi RM, Colditz GA, Wang Y, Collins LC, Hu R, Rosner B, et al. Expression of IGF1R in normal breast tissue and subsequent risk of breast cancer. Breast Cancer Res Treat. 2011;128:243–50.CrossRefPubMedPubMedCentral
7.
8.
Ter Braak B, Siezen CL, Kannegieter N, Koedoot E, van de Water B, van der Laan JW. Classifying the adverse mitogenic mode of action of insulin analogues using a novel mechanism-based genetically engineered human breast cancer cell panel. Arch Toxicol. 2014;88:953–66.CrossRefPubMed
9.
Kellerer M, Haring HU. Insulin analogues: impact of cell model characteristics on results and conclusions regarding mitogenic properties. Exp Clin Endocrinol Diabetes. 2001;109:63–4.CrossRefPubMed
10.
Gallagher EJ, Alikhani N, Tobin-Hess A, Blank J, Buffin NJ, Zelenko Z, et al. Insulin receptor phosphorylation by endogenous insulin or the insulin analog AspB10 promotes mammary tumor growth independent of the IGF-I receptor. Diabetes. 2013;62:3553–60.CrossRefPubMedPubMedCentral
11.
Tennagels N, Welte S, Hofmann M, Brenk P, Schmidt R, Werner U. Differences in metabolic and mitogenic signalling of insulin glargine and insulin aspart B10 in rats [corrected]. Diabetologia. 2013;56:1826–34.CrossRefPubMedPubMedCentral
12.
Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G. Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice. Int J Toxicol. 2002;21:171–9.CrossRefPubMed
13.
14.
Nagel JM, Staffa J, Renner-Muller I, Horst D, Vogeser M, Langkamp M, et al. Insulin glargine and NPH insulin increase to a similar degree epithelial cell proliferation and aberrant crypt foci formation in colons of diabetic mice. Horm Cancer. 2010;1:320–30.CrossRefPubMed
15.
Ruiter R, Visser LE, van Herk-Sukel MP, Coebergh JW, Haak HR, Geelhoed-Duijvestijn PH, et al. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51–62.CrossRefPubMed
16.
Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732–44.CrossRefPubMedPubMedCentral
17.
Buchs AE, Silverman BG. Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study. Metabolism. 2011;60:1379–85.CrossRefPubMed
18.
Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52:1745–54.CrossRefPubMed
19.
Kostev K. Risk of breast cancer in patients on long-acting insulin analogues in comparison with those on human insulin. Diabetologia. 2012;55:1554–5.CrossRefPubMed
20.
Fagot JP, Blotiere PO, Ricordeau P, Weill A, Alla F, Allemand H. Does insulin glargine increase the risk of cancer compared with other basal insulins?: a French nationwide cohort study based on national administrative databases. Diabetes Care. 2013;36:294–301.CrossRefPubMedPubMedCentral
21.
Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755–65.CrossRefPubMedPubMedCentral
22.
van Staa TP, Patel D, Gallagher AM, de Bruin ML. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia. 2012;55:654–65.CrossRefPubMed
23.
Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766–77.CrossRefPubMed
24.
Dejgaard A, Lynggaard H, Rastam J, Krogsgaard TM. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia. 2009;52:2507–12.CrossRefPubMed
25.
Ljung R, Talback M, Haglund B, Jonasson JM, Gudbjornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies - a three-year population-based observation. Acta Oncol. 2011;50:685–93.CrossRefPubMed
26.
Gerstein HC, Bosch J, Dagenais GR, Diaz R, Jung H, Maggioni AP, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.CrossRefPubMed
27.
Janghorbani M, Dehghani M, Salehi-Marzijarani M. Systematic review and meta-analysis of insulin therapy and risk of cancer. Horm Cancer. 2012;3:137–46.CrossRefPubMed
28.
Scheer N, Snaith M, Wolf CR, Seibler J. Generation and utility of genetically humanized mouse models. Drug Discov Today. 2013;18:1200–11.CrossRefPubMed
29.
30.
Wijnhoven SW, Zwart E, Speksnijder EN, Beems RB, Olive KP, Tuveson DA, et al. Mice expressing a mammary gland-specific R270H mutation in the p53 tumor suppressor gene mimic human breast cancer development. Cancer Res. 2005;65:8166–73.CrossRefPubMed
31.
Wijnhoven SW, Speksnijder EN, Liu X, Zwart E, van Oostrom CT, Beems RB, et al. Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage. Cancer Res. 2007;67:4648–56.CrossRefPubMed
32.
Derksen PW, Braumuller TM, van der Burg E, Hornsveld M, Mesman E, Wesseling J, et al. Mammary-specific inactivation of E-cadherin and p53 impairs functional gland development and leads to pleomorphic invasive lobular carcinoma in mice. Dis Model Mech. 2011;4:347–58.CrossRefPubMedPubMedCentral
33.
Chignola R, Foroni RI. Estimating the growth kinetics of experimental tumors from as few as two determinations of tumor size: implications for clinical oncology. IEEE Trans Biomed Eng. 2005;52:808–15.CrossRefPubMed
34.
Cardiff RD, Anver MR, Gusterson BA, Hennighausen L, Jensen RA, Merino MJ, et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene. 2000;19:968–88.CrossRefPubMed
35.
36.
Radaelli E, Arnold A, Papanikolaou A, Garcia-Fernandez RA, Mattiello S, Scanziani E, et al. Mammary tumor phenotypes in wild-type aging female FVB/N mice with pituitary prolactinomas. Vet Pathol. 2009;46:736–45.CrossRefPubMed
37.
Besic N, Satej N. Insulin glargine versus other types of basal insulin-clinical and tumor characteristics in patients with breast carcinoma. BMC Res Notes. 2013;6:416.CrossRefPubMedPubMedCentral
38.
Hvid H, Blouin MJ, Birman E, Damgaard J, Poulsen F, Fels JJ, et al. Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PLoS One. 2013;8:e79710.CrossRefPubMedPubMedCentral
39.
Klarenbeek S, van Miltenburg MH, Jonkers J. Genetically engineered mouse models of PI3K signaling in breast cancer. Mol Oncol. 2013;7:146–64.CrossRefPubMed
Metadata
Title
Mammary gland tumor promotion by chronic administration of IGF1 and the insulin analogue AspB10 in the p53R270H/+WAPCre mouse model
Authors
Bas ter Braak
Christine Siezen
Ewoud N Speksnijder
Esmee Koedoot
Harry van Steeg
Daniela CF Salvatori
Bob van de Water
Jan Willem van der Laan
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2015
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-015-0518-y

Other articles of this Issue 1/2015

Breast Cancer Research 1/2015 Go to the issue

Research article

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth

Research article

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

Research article

Background risk of breast cancer and the association between physical activity and mammographic density

Research article

Changes in insulin receptor signaling underlie neoadjuvant metformin administration in breast cancer: a prospective window of opportunity neoadjuvant study

Research article

The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831

Review

Invasive lobular carcinoma of the breast: morphology, biomarkers and ’omics
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits