The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

TY - JOUR

T1 - The association of diabetes mellitus and insulin treatment with expression of insulin-related proteins in breast tumors

AU - Bronsveld, Heleen K.

AU - De Bruin, Marie L.

AU - Wesseling, Jelle

AU - Sanders, Joyce

AU - Hofland, Ingrid

AU - Jensen, Vibeke

AU - Bazelier, Marloes T.

AU - ter Braak, Bas

AU - de Boer, Anthonius

AU - Vestergaard, Peter

AU - Schmidt, Marjanka K.

PY - 2018

Y1 - 2018

N2 - Background: The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues). Methods: Immunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms. Results: We found no significant differences in expression of any of the proteins in breast tumors of women with (n=211) and without diabetes (n=101). Among women with diabetes, insulin use (n=53) was significantly associated with higher tumor protein expression of IGF1R (OR=2.36; 95%CI:1.02-5.52; p=0.04) and p-mTOR (OR=2.35; 95%CI:1.13-4.88; p=0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p=0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR=5.10; 95%CI:1.36-19.14; p=0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated. Conclusions: In our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.

AB - Background: The insulin receptor (INSR) and the insulin growth factor 1 receptor (IGF1R) play important roles in the etiology of both diabetes mellitus and breast cancer. We aimed to evaluate the expression of hormone and insulin-related proteins within or related to the PI3K and MAPK pathway in breast tumors of women with or without diabetes mellitus, treated with or without insulin (analogues). Methods: Immunohistochemistry was performed on tumor tissue of 312 women with invasive breast cancer, with or without pre-existing diabetes mellitus, diagnosed in 2000-2010, who were randomly selected from a Danish breast cancer cohort. Women with diabetes were 2:1 frequency matched by year of birth and age at breast cancer diagnosis to those without diabetes. Tumor Microarrays were successfully stained for p-ER, EGFR, p-ERK1/2, p-mTOR, and IGF1R, and scored by a breast pathologist. Associations of expression of these proteins with diabetes, insulin treatment (human insulin and insulin analogues) and other diabetes medication were evaluated by multivariable logistic regression adjusting for menopause and BMI; effect modification by menopausal status, BMI, and ER status was assessed using interactions terms. Results: We found no significant differences in expression of any of the proteins in breast tumors of women with (n=211) and without diabetes (n=101). Among women with diabetes, insulin use (n=53) was significantly associated with higher tumor protein expression of IGF1R (OR=2.36; 95%CI:1.02-5.52; p=0.04) and p-mTOR (OR=2.35; 95%CI:1.13-4.88; p=0.02), especially among women treated with insulin analogues. Menopause seemed to modified the association between insulin and IGF1R expression (p=0.07); the difference in IGF1R expression was only observed in tumors of premenopausal women (OR=5.10; 95%CI:1.36-19.14; p=0.02). We found no associations between other types of diabetes medication, such as metformin, and protein expression of the five proteins evaluated. Conclusions: In our study, breast tumors of women with pre-existing diabetes did not show an altered expression of selected PI3K/MAPK pathway-related proteins. We observed an association between insulin treatment and increased p-mTOR and IGF1R expression of breast tumors, especially in premenopausal women. This observation, if confirmed, might be clinically relevant since the use of IGF1R and mTOR inhibitors are currently investigated in clinical trials.

KW - Breast cancer

KW - Diabetes mellitus

KW - Immunohistochemistry

KW - Insulin

KW - Insulin growth factor 1 receptor

KW - MAPK pathway

KW - MTOR

KW - PI3K pathway

U2 - 10.1186/s12885-018-4072-8

DO - 10.1186/s12885-018-4072-8

M3 - Journal article

C2 - 29486734

AN - SCOPUS:85042558452

SN - 1471-2407

VL - 18

JO - BMC Cancer

JF - BMC Cancer

M1 - 224

ER -