Unravelling the link between diabetes, insulin treatment and breast cancer

Abstract

Objective The aims of this thesis were to assess whether diabetes, and specifically insulin treatment, is associated with breast cancer development and breast cancer subtypes, and to investigate potential mechanisms involved. Methods Using the Clinical Practice Research Datalink (CPRD) we described trends in incidence rates of breast cancer in women with and without type 2 diabetes in the United Kingdom over a period of 24 years. To further understand how women with diabetes might have a higher risk for breast cancer we evaluated whether insulin and insulin analogues might contribute to an increased risk of breast cancer in women with diabetes. A quantitative and qualitative review of published in vitro, in vivo and epidemiological evidence on this postulated association, as well as on plausible mechanisms involved, were carried out. Based on the results of this systematic review, we generated hypotheses that were addressed in studiesof breast tumors of women with or without diabetes. We used data and tumor tissue from primary invasive breast cancer patients that were randomly selected from an existing nationwide hospital-based cohort in Denmark. We determined clinical-pathological characteristics of insulin and non-insulin treated women with diabetes compared to women without diabetes, and we determined whether these women develop specific breast cancer subtypes defined by clinically used immunohistochemical tumor markers (ER/PR/HER2). Furthermore, we studied protein- and gene expression within or related to the insulin signaling pathway (PI3K/MAPK) of tumors of women with diabetes and specifically those who used insulin (analogues). Results We found using the CPRD data that incidence rates of breast cancer among women with type 2 diabetes in the UK remained stable between 1989-2012, the incidence rate was approximately 150 per 100,000 women years. The breast cancer incidence in women with diabetes was comparable to women without diabetes. Based on the literature review, we concluded that there is no compelling evidence that any of the clinically available insulin analogues, nor human insulin, increases breast cancer risk. Overall, the data suggested that insulin treatment is not involved in breast tumor initiation, but might induce breast tumor progression by upregulating mitogenic signaling pathways (e.g. MAPK/PI3K). In the studies of breast tumors of Danish women, we found some indication that IGF1R and p-MTOR are over-expressed in tumors of insulin users and hormonal receptors are under-expressed in tumors of premenopausal women with diabetes, characteristics that are typically associated with a poor prognosis. However, based on genes expression analyses these findings were not confirmed. Conclusions Our studies show that insulin or insulin analogue treatment in patients with diabetes is not associated with an increased risk of breast cancer. There is also no compelling evidence that women with diabetes treated with or without insulin develop different breast cancer subtypes compared to women without diabetes. Altogether, it is unlikely that diabetes itself, insulin or insulin analogues strongly affect different pathways involved in breast tumor development.