IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors

Marc A. Becker, Xiaonan Hou, Sean C. Harrington, S. John Weroha, Sergio E. Gonzalez, Kristina A. Jacob, Joan M. Carboni, Marco M. Gottardis, Paul Haluska

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Purpose: To improve the significance of insulin-like growth factor-binding protein 5 (IGFBP-5) as a prognostic and potentially predictive marker in patients with breast cancer. Experimental Design: Increased IGFBP-5 expression was identified in MCF-7 cells resistant (MCF-7R4) to the IGF-1R/insulin receptor (InsR) inhibitor BMS-536924 and its role examined by targeted knockdown and overexpression in multiple experimental models. Protein expression of IGFBP-5 was measured by immunohistochemistry in a cohort of 76 patients with breast cancer to examine correlative associations with invasive tumor fraction and outcome. The use of a combined IGFBP-5/IGFBP-4 (BPR) expression ratio was applied to predict anti-IGF-1R/InsR response in a panel of breast cancer lines and outcome in multiple breast tumor cohorts. Results: IGFBP-5 knockdown decreased BMS-536924 resistance in MCF-7R4 cells, whereas IGFBP-5 overexpression in MCF-7 cells conferred resistance. When compared with pathologically normal reduction mammoplasty tissue, IGFBP-5 expression levels were upregulated in both invasive and histologically normal adjacent breast cancer tissue. In both univariate and multivariate modeling, metastasis-free survival, recurrence free survival (RFS), and overall survival (OS) were significantly associated with high IGFBP-5 expression. Prognostic power of IGFBP-5 was further increased with the addition of IGFBP-4 where tumors were ranked based upon IGFBP-5/IGFBP-4 expression ratio (BPR). Multiple breast cancer cohorts confirm that BPR (high vs. low) was a strong predictor of RFS and OS. Conclusion: IGFBP-5 expression is a marker of poor outcome in patients with breast cancer. An IGFBP-5/ IGFBP-4 expression ratio may serve as a surrogate biomarker of IGF pathway activation and predict sensitivity to anti-IGF-1R targeting.

Original languageEnglish (US)
Pages (from-to)1808-1817
Number of pages10
JournalClinical Cancer Research
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Becker, M. A., Hou, X., Harrington, S. C., Weroha, S. J., Gonzalez, S. E., Jacob, K. A., Carboni, J. M., Gottardis, M. M., & Haluska, P. (2012). IGFBP ratio confers resistance to IGF targeting and correlates with increased invasion and poor outcome in breast tumors. Clinical Cancer Research, 18(6), 1808-1817. https://doi.org/10.1158/1078-0432.CCR-11-1806