ALTERED SERUM LEVELS OF INSULIN-LIKE-GROWTH-FACTOR BINDING-PROTEINS IN BREAST-CANCER PATIENTS

Background: Insulin-like growth factor 1 (IGF-1) has mitogenic propert ies for breast cancer cell lines and has been proposed to be an import ant factor in breast carcinogenesis. We hypothesized that differences in IGF-1 or its binding proteins might increase susceptibility to brea st cancer. This case-control study was designed to investigate whether patients with breast cancer have altered levels of either IGF-1 or it s intermediary modulatory proteins, the IGF binding proteins (BP). Met hods: serum was collected from 90 patients (63 with breast cancer and 27 with benign breast disease) after an overnight fast and before surg ery. IGF-1, BP1, and BP3 levels were determined by immunoradiometric a ssays. In a subset of 66 patients, Western ligand blots were also perf ormed for a semiquantitative measurement of functioning BP levels. A f orward stepwise logistic regression model to adjust for other confound ing variables (age, menopausal status, parity, age at menarche, use of oral contraceptives, history of breast biopsy, family history of brea st cancer, hormone replacement therapy, and body-mass index) was used in the multivariate analysis. Results: Serum IGF-1 levels were similar in cases and controls. However, levels of BP3 (p < 0.001), BP4 (p < 0 .01), and BP1 (p < 0.05) were significantly associated with risk of br east cancer. The level of BP3 was the most significant factor predicti ve of breast cancer. The odds ratio for breast cancer in women with BP 3 levels >2066 ng/ml was 0.18 (95% CI, 0.05-0.55). Correspondingly, wo men with BP1 levels higher than 39 ng/ml had an odds ratio of 0.21 (95 % CI, 0.07-0.68) for breast cancer. When considering only cancer patie nts (n = 63), decreasing levels of BP4 (p < 0.01) and increasing level s of BP1 (p < 0.02) were significantly associated with progesterone re ceptor positivity (PR+) in the tumor. The odds ratio of PR+ in patient s with BP1 levels higher than 34 ng/ml was 7.49 (95% CI, 1.5-37.4). Be tter grade of tumor (well and moderately differentiated) was observed in patients with higher levels of BP3 (p < 0.03). Conclusions: Distinc t differences in BP profiles exist among patients with breast cancer a nd also among those with high-grade, hormonal receptor-negative tumors , These findings suggest that the bioavailability of IGF-1 as mediated by its binding proteins may participate in both breast carcinogenesis and selection of more aggressive breast carcinomas.