Prognostic Significance of Insulin-like Growth Factor-Binding Protein Expression in Axillary Lymph Node-Negative Breast Cancer

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Abstract
Background: Cellular proliferation, as measured by S-phase fraction, is an important predictor of breast cancer prognosis. The insulin-like growth factors (IGFs) have been shown to regulate proliferation in both normal and neoplastic cells by interacting with specific cell surface receptors. In addition to these receptors, high-affinity extracellular binding proteins also modulate IGF action. These insulin-like growth factor-binding proteins (IGFBPs) could influence breast cancer growth and, like other biological parameters of proliferation, could be related to prognosis. Purpose: To test whether IGFBP expression was related to other biological parameters and disease-free survival, we measured IGFBP expression in 238 lymph node-negative primary breast cancer specimens. Methods: Proteins were extracted from breast cancer specimens and analyzed by semiquantitative IGF-I ligand blotting for IGFBP expression. IGFBP expression levels were compared to tumor size, age, S-phase fraction, DNA ploidy, and estrogen and progesterone receptor expression by Spearman correlation. Results: Binding protein (BP)-2, BP-3, BP-4, and BP-5 were identified in breast cancer extracts. Estrogen receptor expression was positively correlated with BP-2 (Spearman correlation coefficient, r s = .262; P = .0001), BP-4 ( r s = .313; P = .0001), and BP-5 ( r s = .242; P = .0002). Similar correlations between progesterone receptor and BP-2, BP-4, and BP-5 were also found. BP-3 was inversely correlated with age ( r s = −.251, P = .0001). BP-4 was weakly inversely correlated with tumor size ( r s = −.141; P = .0295) and S-phase fraction ( r s = −.216; P = .0025). Since tumor size and S-phase fraction are powerful predictors of prognosis in node-negative breast cancer, we examined the value of BP-4 as a predictor of disease-free survival. When stratified by tumor size, patients with large (>2 cm) tumors that expressed low levels of BP-4 had improved survival when compared with patients with large tumors and high BP-4 levels ( P = .001). Conclusions: IGFBPs can be detected in breast cancer specimens, and their level of expression correlates with other known biological parameters of breast cancer. Large tumors with low levels of BP-4 have relatively favorable prognoses. Implications: These data suggest that the IGFBPs may play a role in breast cancer biology and that BP-4 levels, analyzed in conjunction with tumor size, may have prognostic significance. [J Natl Cancer Inst 86: 1785–1789, 1994]

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