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Insulin-like Growth Factor Binding Protein-related Protein 1 Inhibits Proliferation of MCF-7 Breast Cancer Cells via a Senescence-like Mechanism¹

Department of Pathology, University of Washington School of Medicine, Seattle, Washington 98195 [H-M. P. W., M. P., K. S.]; Research Service and Geriatric Research, Education, and Clinical Center, Veterans Administration Puget Sound Health Care System, Tacoma, Washington 98493 [R. S. B.]; and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, Washington 98195 [R. S. B., L. S. Q.]

Elevated insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) mRNA in senescent human mammary epithelial cells suggested that the IGFBP-3 gene product may inhibit cell proliferation. To test this hypothesis, we used a retroviral vector to express IGFBP-rP1 cDNA in the IGFBP-rP1-deficient MCF-7 breast cancer cell line. Compared with control vector-transduced cells, cumulative cell numbers for IGFBP-rP1-transduced polyclonal or clonal cell cultures were reduced by 39 and 74%, respectively, after 1 week. Medium conditioned by IGFBP-rP1-producing cultures reduced cumulative cell numbers in parental MCF-7 cultures by 20% compared with medium from cultures of a control vector-transduced cell line. Nuclear fragmentation analysis and cell proliferation assays completed in the presence of the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone excluded apoptosis as the responsible mechanism. The percentage of cells containing senescence-associated ß-galactosidase activity was doubled compared with control cell cultures. Flow cytometry analysis indicated that twice as many noncycling cells were present in the IGFBP-rP1-transduced MCF-7 cell cultures compared with controls. These findings indicate that IGFBP-rP1 is an inhibitor of MCF-7 breast cancer cell proliferation and may act via a cellular senescence-like mechanism.

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