Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Becker MA

PROVIDER: S-EPMC3306532 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Becker Marc A MA Hou Xiaonan X Harrington Sean C SC Weroha S John SJ Gonzalez Sergio E SE Jacob Kristina A KA Carboni Joan M JM Gottardis Marco M MM Haluska Paul P

Clinical cancer research : an official journal of the American Association for Cancer Research 20120127 6

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 immunohis ...[more]

PMID: 22287600

Similar Datasets

Project description:Insulin-like growth factor 1 (IGF-1) has been associated with osteoporosis, cardiovascular disease, cancer, neurodegenerative diseases, and mortality in middle and older aged adults. Cross-sectionally, IGF-1 decreases with age and levels of IGF-1 are markedly different between individuals. However, little is known about intra-individual trajectories of IGF-1. We examined baseline and serial measures of plasma total IGF-1, IGF binding protein (IGFBP)-3, and their ratio, which is a proxy for bioavailable IGF-1, among 1618 adults, aged 50-95, enrolled in the Mayo Clinic Study of Aging. At baseline, IGF-1 and IGFBP-3 were strongly correlated (r?=?0.62, p?<?0.001). Total IGF-1 and IGFBP-3 decreased across age, while the ratio of IGF-1/IGFBP-3 increased across age. This pattern was consistent across ages at baseline and intra-individually over an average 2.3?years follow-up (range?=?10?months-5.6?years). In age-adjusted linear regression models, baseline levels of total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 varied by participant characteristics (sex, BMI, gait speed), medical comorbidities (Charlson comorbidity index score, hypertension, diabetes, and cardiovascular disease), and hormone replacement therapy use in women. High interclass correlation coefficients (ICCs) suggest little intra-individual variability in levels of total IGF-1 (ICC?=?0.84), IGFBP-3 (ICC?=?0.88), and IGF-1/IGFBP-3 (ICC?=?0.81) over time. In mixed effects models that specified age as a time scale, men showed greater decreases in total IGF-1 and IGFBP-3 with age, while more comorbidities and decreasing gait speed were associated with increasing IGFBP-3. In sex-stratified models, trajectories of total IGF-1, IGFBP-3, and IGF-1/IGFBP-3, as a function of participant demographics, health characteristics, and medical conditions, differed between men and women. These results suggest that change in levels of plasma total IGF-1, IGFBP-3, and IGF-1/IGFBP-3 are associated with demographics, health characteristics, and medical conditions, and that the trajectories of change differ by sex. Future research should consider how IGF-1 and IGFBP-3 might be useful in research or clinic, paying particular attention to how sex may impact levels as a function of demographics, health characteristics, and medical conditions.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets