IGFBP-7 expression in human breast cancer and association with proliferation and cell cycle aberrations

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The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer, potentially leading to IGF1 receptor activation and uncontrolled tyrosine kinase signalling. In addition to defects in proteins controlling cell cycle checkpoints, this type of aberration could affect tumor growth and survival, thereby influencing both tumor aggressiveness and potential response to treatments. We have earlier shown that the T1A12/mac25 protein, which is identical to the insulin-like binding protein (IGFBP-7), is differentially expressed in breast cancer cells compared with normal cells. The gene product seemed to be lost in the progression from premalignancy to invasive breast cancer and loss of heterozygosity (LOH) of the 4q12-13 region was frequently observed in invasive cancers, suggesting a suppressor-life function for IGFB-7. In 104 invasive breast cancers arranged in a tissue-array system, all with known status of cell-cycle aberrations and clinico-pathological data, the expression of IGFB-7 was monitored using immunohistochemistry. Cytoplasmic staining of variable intensity was observed in the tumors and 14% lacked IGFBP-7 staining, 20% had low staining, 32% intermediate staining and 34% strong staining. Low IGFB-7 was associated with high cyclin E expression, retinoblastoma protein inactivation, low bcl-2 and poorly differentiated tumors. There was further a significantly impaired prognosis for patients with low IGFB-7 protein tumors. Interestingly, IGFB-7 was strongly and inversely associated with proliferation (Ki-67 %) in estrogen receptor-negative tumors, suggesting an important cell-cycle regulatory function for IGFBP-7 separate from the interaction with the estrogen receptor pathway.