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

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 6 Pg. 1808-17 (Mar 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22287600 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BMS 536924
• Benzimidazoles
• Biomarkers, Tumor
• Insulin-Like Growth Factor Binding Protein 5
• Pyridones

Topics

• Adult
• Aged
• Aged, 80 and over
• Benzimidazoles (therapeutic use)
• Biomarkers, Tumor (metabolism)
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Female
• Gene Knockdown Techniques
• Humans
• Insulin-Like Growth Factor Binding Protein 5 (genetics, metabolism)
• Middle Aged
• Neoplasm Invasiveness
• Prognosis
• Pyridones (therapeutic use)