Insulin and IGFs in obesity-related breast cancer.

Obesity and the Metabolic Syndrome are associated with multiple factors that may cause an increased risk for cancer and cancer-related mortality. Factors involved include hyperinsulinemia, hyperglycemia, hyperlipidemia and IGFs. Insulin resistance is also associated with alterations in the levels of proinflammatory cytokines, chemokines, adipokines (leptin, adiponectin) that may also be contributing factors. The insulin family of proteins is ubiquitously expressed and has pleiotropic effects on metabolism and growth. However insulin, IGF-1 and particularly IGF-2 have been identified as tumor promoters in multiple studies. Mouse models have focused on insulin and IGF-1 and their receptors as being involved in tumor progression and metastases. The role of the insulin receptor as either mediating the effects on tumors or as compensating for the insulin-like growth factor receptor has arisen. Its role has been supported by preclinical studies and the importance of insulin resistance and hyperinsulinemia in obesity and early diabetes. Since the focus of this review is the insulin-family we will focus on insulin, IGF-1 and IGF-2.

IGF-II mRNA expression in breast cancer: predictive value and relationship to other prognostic factors.

PURPOSE: Insulin-like growth factor-II (IGF-II) is an important regulator of tumor growth in breast cancer. In this study we have examined the prognostic value of IGF-II mRNA expression in breast cancer and its relationship to other predictive parameters. PATIENTS: Sixty-eight women with infiltrating ductal carcinoma were given the same treatments including mastectomy and antitumoral therapies and followed up for 5 years. RESULTS: The overall 5-year survival rate was 73.5% (55/68). IGF-II mRNA was expressed in 33/64 patients (51.6%) and had no significant impact on survival. The expression of estrogen receptor (ER) and progesterone receptor (PgR) did not significantly affect the 5-year survival, but in the presence of an IGF-II mRNA signal, the survival of ER- and PgR-negative patients (n=9) was lower than that of ER- and PgR-positive patients (n=15), although the difference was not significant. The 5-year survival was not significantly different between Ki-67-positive and negative patients, but in the IGF-II positive group Ki-67-positive patients (n=7) had a significantly poorer prognosis than Ki-67-negative patients (n=26). The expression of p53 protein was associated with a poorer prognosis: 6/11 (54.5%) p53-positive patients died in the first 26 months of follow-up and 5 of these 6 patients (83.3%) also had positive IGF-II mRNA expression. CONCLUSIONS: IGF-II mRNA expression per se is not an independent predictive factor in breast cancer but may be a marker of poor prognosis when associated with other prognostic factors such as Ki-67 index and p53 expression.