Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 2  |  Page : 295-299

The expression difference of insulin-like growth factor 1 receptor in breast cancers with or without diabetes


Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Date of Web Publication7-Jul-2015

Correspondence Address:
Liu Ji-Yan
Department of Medical Oncology, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan Province
China
Login to access the Email id

Source of Support: The equipments were supported by Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, Conflict of Interest: None


DOI: 10.4103/0973-1482.138195

Rights and Permissions
 > Abstract 

Context: The insulin-like growth factor (IGF) and insulin receptors' (IR) axes play important roles in both breast cancer and diabetes mellitus.
Aim: We tend to explore the expression characteristics of proteins in IGF/IR axis in breast cancer with type 2 diabetes mellitus (T2DM).
Settings and Design: We conducted a case-control investigation of T2DM and non-diabetes (n = 40, 1:1) in breast cancer patients.
Materials and Methods: Some important molecules of IGF/IR axis were detected in breast cancer tissues by immunohistochemical staining. The multivariable analyses of the relationship of clinicopathological characters with the significant molecules were also detected.
Statistical Analysis Used: The results were statistically evaluated by Statistical Package for the Social Sciences (SPSS version 17.0) software. Chi-square test and logistic regression are used.
Results: Higher expression of IGF 1 receptor (IGF1R) was found in breast cancers of patients with T2DM, compared those without diabetes (P = 0.044). Negative expression of human epidermal growth factor receptor 2 (Her2) was found to be associated with higher expression of IGF1R in the breast cancers of patients with T2DM. There were no differences found in the expression of proteins of IGF-1, IGF-2, IGF-binding protein 3 (IGFBP3), IR, insulin receptor substrate (IRS)-1, IRS-2 and mammalian target of rapamycin (mTOR) between T2DM group and non-diabetes group.
Conclusion: Our study found that breast cancer with T2DM had a higher expression of IGF1R, and the higher IGF1R was associated with negative Her2 expression.

Keywords: Breast cancer, human epidermal growth factor receptor 2, insulin-like growth factor 1 receptor, type 2 diabetes mellitus


How to cite this article:
Xin C, Jing D, Jie T, Wu-Xia L, Meng Q, Ji-Yan L. The expression difference of insulin-like growth factor 1 receptor in breast cancers with or without diabetes. J Can Res Ther 2015;11:295-9

How to cite this URL:
Xin C, Jing D, Jie T, Wu-Xia L, Meng Q, Ji-Yan L. The expression difference of insulin-like growth factor 1 receptor in breast cancers with or without diabetes. J Can Res Ther [serial online] 2015 [cited 2019 Nov 14];11:295-9. Available from: http://www.cancerjournal.net/text.asp?2015/11/2/295/138195


 > Introduction Top


Breast cancer is the most common cancer in women, worldwide. [1] Interestingly, people with type 2 diabetes mellitus (T2DM) are at higher risk for breast cancer. [2] Accumulating data suggest that diabetes has an impact on prevalence, progression, and prognosis of breast cancer. [3],[4],[5],[6] The two diseases shared same risk factors and use of anti-diabetic drugs make an effect on cancer patients with diabetes. [6],[7],[8],[9] Increasing evidence shows that insulin-like growth factor/insulin receptors (IGF/IR) signaling may play important roles in the pathogenesis of both diabetes and cancers. [10],[11] In this study, we assessed the expression of proteins of IGF/IR system in breast cancer tissues of patients with or without T2DM.


 > Materials and methods Top


This study was retrospectively performed on primary breast cancer patients who underwent mastectomy at Hospital from December 2008 to November 2010. Inclusion criteria were histological or cytological confirmation of breast cancers; patients who had undergone radical surgical removal of primary lesions; newly diagnosed breast cancer without radiotherapy or chemotherapy before surgery; pre-existing T2DM before the diagnosis of breast cancer. Cases with multiple cancers, breast implant before operation, insufficient clinical or pathological data were excluded from the study. Control cases (1:1) were screened from non-T2DM patients with the same inclusion and exclusion criteria, except for the diagnosis of T2DM, and the morning fasting glucose of control subjects should not exceed 5.9 mmol/L. Age (±3 years), pathological type, stage, the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (Her2) were included for the match criteria. Clinicopathological data, such as age, pathological type, the greatest dimension of the tumors, lymph nodes or distant metastasis, stage, blood glucose, body mass index (BMI), the status of ER, progesterone receptor (PR) and Her2 were noted. We indicate the procedures followed, which are in accordance with the ethical standards.

The paraffin-embedded breast cancer blocks of included patients were collected. Immunohistochemical studies were performed on 4 μm sections. Antigen retrieval was carried out with citrate buffer, pH 6.0, and heating in microwave oven for 15 min. Subsequently, the sections were incubated with primary antibodies at 4°C overnight respectively (IGF1R clone Ab131476, at 1:200; IGF-1 clone ab9572, IGF-2 clone ab9574, insulin receptor substrate 1 (IRS-1) clone ab52167 and mTOR clone ab2732, at 1:100; IR clone ab5500, IRS-2 clone ab46811 at 1:50; and IGFBP3 clone ab76001, at 1:40). All primary antibodies were rabbit polyclonal and purchased from Abcam, Hong Kong, China. Then, the sections were incubated for one hour at 37°C by PV6001 Two-Step immunohistochemistry Detection Reagent (ZSJQ-BIO, Bei Jing, China). After washed with phosfate-buffered saline (PBS), the sections were colored by 3, 3[TAG:2][/TAG:2]

-diaminobenzidine, and were counterstained by hematoxylin.

The sections were examined by an investigator who was unaware of the patient group. Each section was examined in a high power field at 200 times magnification. Percentage of positive tumor cells and staining intensity are all taken into account. We chose five views from one section, percentage of positive tumor cells of every view are recorded and the average value of percentage are remained in employment. Staining intensity are carried out with 0 (absent), 1 (weak), 2 (moderate), 3 (strong). We consider the value (staining intensity multiply by the average percentage) as the scores for expression rank: 0, score ≤0.6; 1+, 0.6 < score ≤ 1.4; 2+, 1.4 < score ≤2.2; 3+, 2.2 < score ≤ 3.

The results were statistically evaluated by Statistical Package for the Social Sciences (SPSS version 17.0) software. We compared the immunohistochemical staining by Chi-square test. Data for pathological type, tumor size, node status, grade, BMI, blood glucose, ER status, PR status and Her2 status were obtained as baseline variables. We used the logistic regression to assess and control the simultaneous contribution of baseline covariates in multivariable analyses. A P < 0.05 was considered statistically significant.


 > Results Top


Sixty-five patients met the inclusion criteria, of those, twenty-five patients were excluded because of the data deficiency. Then 40 cases with T2DM were included for analysis and they were paired with the nearest characteristics by control subjects. Clinical and pathological characteristics of the case and the control subjects are showed in [Table 1].
Table 1: Clinicopathological characteristics of the breast cancer with T2DM and paired patients without diabetes (n=40)

Click here to view


Mammalian target of rapamycin (mTOR) and IGF-2 showed mostly in cytoplasmic and partly in membrane staining with a positive rates of 70% and 87.5%. IGF-1, IGF-binding protein-3 (IGFBP3), insulin receptor substrate (IRS)-1, IRS-2 and IR were stained mainly in cytoplasmic and a small part in membrane and nucleus with a positive rates of 77.5%, 70%, 75%, 66.25% and 85%. IGF1R was expressed in 82.5% of samples and mostly found in cytoplasmic and membrane. The expression of the proteins in breast cancers is showed in [Figure 1].
Figure 1: The representative figures of expression of the proteins in breast cancers (substance P (SP) × 200)

Click here to view


Difference in the IGF1R expression of breast cancer tissues between patients with and without T2DM was observed. High expression (2+ and 3+) of IGF1R was observed more in breast cancer tissues of patients with T2DM than those without T2DM (P = 0.044). The expression differences of IGF-1, IGF-2, IGFBP3, IRS-1, IRS-2, IR and mTOR were not found between patients with and without T2DM [Table 2].
Table 2: The expression differences of proteins in IGF/IR - signaling pathway between breast cancers with and without diabetes

Click here to view


To clarify the potential clinicopathological factors associated with higher IGF1R expression in T2DM group, patients with an immunohistochemistry score of ≤1.4 were considered as negative to weak immunoreactivity and those with a score of >1.4 as moderate to strong immunoreactivity. Correlation between IGF1R expression and the clinicopathological characteristics of patients with breast cancer and diabetes are shown in [Table 3]. Negative Her2 expression was found to be associated with higher IGF1R expression. There was no correlation between IGF1R expression and other clinicopathological factors, such as size of tumor, lymph node (LN) metastasis, pathological type, blood glucose, BMI, ER and PR status.
Table 3: Correlation of the IGF - 1R expression and clinicopathological factors in breast cancer with T2DM

Click here to view



 > Discussion Top


The IGF/IR families are important growth factor systems, which have powerful anti-apoptotic effects and also act in both the development of the organism and the maintenance of normal function of many cells of the body. The IGF/IR families are reported to play important roles in cancer development, meantime, the IGF/IR axis might influence diabetes risk, and IGF-1 may reduce blood glucose levels. [12],[13],[14],[15] However, it is still unclear whether IGF/IR families play a role in carcinogenesis of diabetes patients. In this study, the expression differences of some important molecules in IGF/IR families were examined in breast cancer from patients with or without diabetes.

The expression of IGF1R was found difference between breast cancer groups with and without T2DM, the breast cancer tissues of patients with T2DM showed higher expression of IGF1R. As we known, in T2DM, insulin resistance leads to chronic hyperinsulinemia, and insulin can indirectly increase hepatic IGF-1production, [16],[17] thus, chronic hyperinsulinemia is associated with elevated IGF-1 levels. [13],[18] Additionally, increased levels of insulin lead to increased formation of hybrid receptors and may lead to insulin binding to the IGF1R. [19] All these suggested that the IGF signaling is active in insulin resistance status of diabetes. In our study, higher IGF1R expression in breast cancer with T2DM was observed, which suggested that IGF/IR signaling might play an important role in breast cancer development during the course of diabetes.

In the present study, we found higher IGF1R level was associated with negative Her2 expression in breast cancer of T2DM group. As we known, IR and IGF1R signaling act through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/the mammalian target of Rapamycin (mTOR), PI3K/Akt/mTOR signaling pathway and mediates the promoting effect of cancer progression. [13] The Her2 involves the same downstream signaling via PI3K, AKT and mTOR. [20],[21],[22] Previous study reported that breast cancer cells transfected with Her2 showed downregulation of IGF1R, while trastuzumab-resistant cells showed 3-fold higher expression of IGF 1R. [23] Furthermore, some studies led to the concept that IGF1Rover-expression may be associated with reduced response to trastuzumab. [24],[25] All these evidences suggested that IGF1R might be an alternative mechanism to active PI3K/AKT/mTOR signaling pathway in Her2 negative breast cancer. In our study, higher IGF1R expression was found in negative Her2 expression breast cancers in T2DM group, which supports that IGF1R signaling might be an another important way of breast cancer development, especially in Her2 negative status.

The study is a preliminary exploration of IGF1R-signaling pathway in breast cancer development with diabetes. In the study, immunohistochemical staining was used to analyze the proteins expression of IGF family, further investigation and verification regarding the mechanism are conducting. Meanwhile, besides breast cancers, elevated expression of IGF1R in non-small cell lung cancer patients with preexisting diabetes was also found, [26] which prompted us to conduct further experiments to explore the role of these molecules in carcinogenesis associated with diabetes.

In conclusion, higher expression of IGF1R was found in breast cancer with T2DM in our study, compared with those without diabetes, and the higher expression of IGF1R is associated with negative Her2 expression in T2DM group. Further studies are being conducted to confirm the role of IGF1R in breast cancer development in diabetes patients.


 > Acknowledgment Top


This work was partly supported by National Natural Science Foundation of China (81272457).

 
 > References Top

1.
Pichard C, Plu-Bureau G, Neves-E Castro M, Gompel A. Insulin resistance, obesity and breast cancer risk. Maturitas 2008;60:19-30.  Back to cited text no. 1
    
2.
Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: A consensus report. Diabetes Care 2010;33:1674-85.  Back to cited text no. 2
    
3.
Cohen DH, LeRoith D. Obesity, type 2 diabetes, and cancer: The insulin and IGF connection. Endocr Relat Cancer 2012;19:27-45.  Back to cited text no. 3
    
4.
Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer 2007;121:856-62.  Back to cited text no. 4
    
5.
Jiralerspong S, Kim ES, Dong W, Feng L, Hortobagyi GN, Giordano SH. Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients. Ann Oncol 2013;24:2506-14.  Back to cited text no. 5
    
6.
Hou G, Zhang S, Zhang X, Wang P, Hao X, Zhang J. Clinical pathological characteristics and prognostic analysis of 1,013 breast cancer patients with diabetes. Breast Cancer Res Treat 2013;137:807-16.  Back to cited text no. 6
    
7.
Tan BX, Yao WX, Ge J, Peng XC, Du XB, Zhang R, et al. Prognostic influence of metformin as first-line chemotherapy for advanced nonsmall cell lung cancer in patients with type 2 diabetes. Cancer 2011;117:5103-11.  Back to cited text no. 7
    
8.
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27:3297-302.  Back to cited text no. 8
    
9.
Xue F, Michels KB. Diabetes, metabolic syndrome, and breast cancer: A review of the current evidence. Am J Clin Nutr 2007;86:823-35.  Back to cited text no. 9
    
10.
Rajpathak SN, He M, Sun Q, Kaplan RC, Muzumdar R, Rohan TE, et al. Insulin-like growth factor axis and risk of type 2 diabetes in women. Diabetes 2012;61:2248-54.  Back to cited text no. 10
    
11.
Shimizu C, Hasegawa T, Tani Y, Takahashi F, Takeuchi M, Watanabe T, et al. Expression of insulin-like growth factor 1receptor in primary breast cancer: Immunohistochemical analysis. Hum Pathol 2004;35:1537-42.  Back to cited text no. 11
    
12.
Chan BT, Lee AV. Insulin receptor substrates (IRSs) and breast tumorigenesis. J Mammary Gland Biol Neoplasia 2008;13:415-22.  Back to cited text no. 12
    
13.
LeRoith D, Roberts CT Jr. The insulin-like growth factor system and cancer. Cancer Lett 2003;195:127-37.  Back to cited text no. 13
    
14.
Schneider HJ, Friedrich N, Klotsche J, Schipf S, Nauck M, Völzke H, et al. Prediction of incident diabetes mellitus by baseline IGF1 levels. Eur J Endocrinol 2011;164:223-9.  Back to cited text no. 14
    
15.
LeRoith D, Yakar S. Mechanisms of Disease: Metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab 2007;3:302-10.  Back to cited text no. 15
    
16.
Amiel SA, Sherwin RS, Hintz RL, Gertner JM, Press CM, Tamborlane WV. Effect of diabetes and its control on insulin-like growth factors in the young subject with type 1 diabetes. Diabetes 1984;33:1175-9.  Back to cited text no. 16
[PUBMED]    
17.
Leung KC, Doyle N, Ballesteros M, Waters MJ, Ho KK. Insulin regulation of human hepatic growth hormone receptors: Divergent effects on biosynthesis and surface translocation. J Clin Endocinol Metab 2000;85:4712-20.  Back to cited text no. 17
    
18.
Renehan AG, Zwahlen M, Minder C, O′Dwyer ST, Shalet SM, Egger M. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. Lancet 2004;363:1346-53.  Back to cited text no. 18
    
19.
Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R. Diabetes and cancer. Endocr Relat Cancer 2009;16:1103-23.  Back to cited text no. 19
    
20.
Esteva FJ, Hortobagyi GN, Sahin AA, Smith TL, Chin DM, Liang SY, et al. Expression of erbB/HER receptors, heregulin and p38 in primary breast cancer using quantitative immunohistochemistry. Pathol Oncol Res 2001;7:171-7.  Back to cited text no. 20
    
21.
Jin Q, Esteva FJ. Cross-talk between the ErbB/HER family and the type I insulin like growth factor receptor signaling pathway in breast cancer. J Mammary Gland Biol Neoplasia 2008;13:485-98.  Back to cited text no. 21
    
22.
Dean-Colomb W, Esteva FJ. HER2-positive breast cancer: Herceptin and beyond. Eur J Cancer 2008;44:2806-12.  Back to cited text no. 22
    
23.
Cornelissen B, McLarty K, Kersemans V, Reilly RM. The level of insulin growth factor-1 receptor expression is directly correlated with the tumor uptake of 111In-IGF-1(E3R) in vivo and the clonogenic survival of breast cancer cells exposed in vitro to trastuzumab (Herceptin). Nucl Med Biol 2008;35:645-53.  Back to cited text no. 23
    
24.
Smith BL, Chin D, Maltzman W, Crosby K, Hortobagyi GN, Bacus SS. The efficacy of Herceptin therapies is influenced by the expression of other erbB receptors, their ligands and the activation of downstream signalling proteins. Br J Cancer 2004;91:1190-4.  Back to cited text no. 24
    
25.
Jerome L, Alami N, Belanger S, Page V, Yu Q, Paterson J, et al. Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. Cancer Res 2006;66:7245-52.  Back to cited text no. 25
    
26.
Ding J, Tang J, Chen X, Men HT, Luo WX, Du Y, et al. Expression characteristics of proteins of the insulin-like growth factor axis in non-small cell lung cancer patients with preexisting type 2 diabetes mellitus. Asian Pac J Cancer Prev 2013;14:5675-80.  Back to cited text no. 26
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Materials and me...>Results>Discussion>Acknowledgment>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed2451    
    Printed45    
    Emailed0    
    PDF Downloaded149    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]