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Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors

Oncogene volume 20, pages 3497–3505 (2001)Cite this article

Abstract

The complex insulin-like growth factor network of ligands, receptors and binding proteins has been shown to be disturbed in breast cancer. In addition to defects in proteins controling cell cycle checkpoints, this type of aberrations could affect tumor growth and survival thereby influencing both tumor aggressiveness and potential response to treatments. We have previously identified the T1A12/mac25 protein, which is identical to the IGFBP-rP1, as a differentially expressed gene product in breast cancer cells compared with normal cells. Here we compare the expression of IGFBP-rP1 in 106 tumor samples with known status of cell cycle aberrations and other clinicopathological data. This was done using a tumor tissue section array system that allows for simultaneous immunohistochemical staining of all samples in parallel. Cytoplasmic staining of variable intensity was observed in most tumors, 15% lacked IGFBP-rP1 staining completely, 20% had weak staining, 32% intermediate and 33% showed strong staining. Low IGFBP-rP1 was associated with high cyclin E protein content, retinoblastoma protein (pRb) inactivation, low bcl-2 protein, poorly differentiated tumors and higher stage. There was a significantly impaired prognosis for patients with low IGFBP-rP1 protein tumors. Interestingly, IGFBP-rP1 showed an inverse association with proliferation (Ki-67%) in estrogen receptor negative tumors as well as in cyclin E high tumors suggesting a separate cell cycle regulatory function for IGFBP-rP1 independent of interaction with the estrogen receptor or the pRb pathway.

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Acknowledgements

We would like to thank Bodil Bäcklund and Britta Lindgren for skilful technical assistance and Martin Lodén for fruitful discussions. This work was supported by grants from the NCIC, Canadian Breast Cancer Research Initiative to A Seth and Swedish Cancer Society and Lion's Cancer research foundation, Umeå University to G Landberg.

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Authors and Affiliations

  1. Division of Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden

    Göran Landberg & Hanna Östlund

  2. Department of Medical Biosciences, Pathology, Umeå University, Sweden

    Niels Hilmer Nielsen & Göran Roos

  3. Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Sweden

    Stefan Emdin

  4. Tumor Biology Center at the University of Freiburg, Germany

    Angelika M Burger

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto and Laboratory of Molecular Pathology, Sunnybrook and Women's College Health Sciences Centre, 76 Greenville Street, Toronto, Ontario, Canada

    Arun Seth

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Landberg, G., Östlund, H., Nielsen, N. et al. Downregulation of the potential suppressor gene IGFBP-rP1 in human breast cancer is associated with inactivation of the retinoblastoma protein, cyclin E overexpression and increased proliferation in estrogen receptor negative tumors. Oncogene 20, 3497–3505 (2001). https://doi.org/10.1038/sj.onc.1204471

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