IGFBP Ratio Confers Resistance to IGF Targeting and Correlates with Increased Invasion and Poor Outcome in Breast Tumors

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

doi:10.1158/1078-0432.ccr-11-1806

Cited by 32 publications

(25 citation statements)

References 27 publications

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“…In transgenic mice, IGFBP5 expression interferes with mammary epithelial development (Tonner et al, 2002). IGFBP5 expression levels have also been shown to be a marker of poor outcome in patients with breast cancer (Becker et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

Seo

Stranger

et al. 2013

Cell

297

317

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Summary Germline determinants of gene expression in tumors are less studied due to the complexity of transcript regulation caused by somatically acquired alterations. We performed expression quantitative trait locus (eQTL) based analyses using the multi-level information provided in The Cancer Genome Atlas (TCGA). Of the factors we measured, cis-acting eQTL saccounted for 1.2% of the total variation of tumor gene expression, while somatic copy number alteration and CpG methylation accounted for 7.3% and 3.3%, respectively. eQTL analyses of 15 previously reported breast cancer risk loci resulted in discovery of three variants that are significantly associated with transcript levels (FDR<0.1). In a novel trans- based analysis, an additional three risk loci were identified to act through ESR1, MYC, and KLF4. These findings provide a more comprehensive picture of gene expression determinants in breast cancer as well as insights into the underlying biology of breast cancer risk loci.

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Section: Discussionmentioning

confidence: 99%

Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

Seo

Stranger

et al. 2013

Cell

297

317

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“…Preclinical models find evidence of correlation between sensitivity to figitumumab or TKI NVP-AEW541 and expression of IRS2, IGFBP5 and MYB in colorectal cancer [86], and expression of IGF-1R, IGF-2 and IRS-1 and -2 in breast and colon models [87,88]. In breast cancer cells resistant to BMS 536924, the IGFBP-5/IGFBP-4 expression ratio was found to correlate with sensitivity to IGF-1R inhibition [89]. Clinical evidence supporting evaluation of IGF axis biomarkers comes from trials in pancreatic cancer, where sensitivity to dalotuzumab (IGF-1R antibody MK-0646) was linked with tumor IGF-1 expression, and to ganitumab with high circulating IGF-1, IGF-2 or IGFBP-3, or low IGFBP-2 [82,90].…”

Section: Can We Identify Who Will Benefit?mentioning

confidence: 99%

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

King

Aleksic

Haluska

et al. 2014

Cancer Treatment Reviews

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123

132

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IGF-1R inhibitors arrived in the clinic accompanied by optimism based on preclinical activity of IGF-1R targeting, and recognition that low IGF bioactivity protects from cancer. This was tempered by concerns about toxicity to normal tissue IGF-1R and cross-reactivity with insulin receptor (InsR). In fact, toxicity is not a show-stopper; the key issue is efficacy. While IGF-1R inhibition induces responses as monotherapy in sarcomas and with chemotherapy or targeted agents in common cancers, negative Phase 2/3 trials in unselected patients prompted the cessation of several Pharma programs. Here, we review completed and on-going trials of IGF-1R antibodies, kinase inhibitors and ligand antibodies. We assess candidate bio-markers for patient selection, highlighting the potential predictive value of circulating IGFs/IGFBPs, the need for standardized assays for IGF-1R, and preclinical evidence that variant InsRs mediate resistance to IGF-1R antibodies. We review hypothesis-led and unbiased approaches to evaluate IGF-1R inhibitors with other agents, and stress the need to consider sequencing with chemotherapy. The last few years were a tough time for IGF-1R therapeutics, but also brought progress in understanding IGF biology. Even failed studies include patients who derived benefit; they should be investigated to identify features distinguishing the tumors and host environment of responders from non-responders. We emphasize the importance of incorporating biospecimen collection into trial design, and wording patient consents to allow post hoc analysis of trial material as new data become available. Such information represents the key to unlocking the potential of this approach, to inform the next generation of trials of IGF signalling inhibitors.

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“…The 2q35 risk locus falls within a 400Kb gene desert bounded by genes TNP1 (MIM: 190231) and DIRC3 (MIM: 608262), nearby two members of the insulin growth factor binding protein family, IGFBP5 and IGFBP2 (MIM: 146731). IGFBP5 plays a critical role in mammary development (7,8) and has been consistently implicated in tumourigenesis (7)(8)(9)(10)(11). The neighbouring intergenic region contains the previously identified breast cancer (MIM: 114480) risk loci, rs13387042 (3) (Genbank: NC_000002 g.217041109A > G), rs16857609 (2)(Genbank: NC_000002 g.217431785C > T), and rs4442975(5) (Genbank: NC_000002 g.217920769G > T) as well as numerous intergenic enhancers, of which many whose function remains elusive.…”

Section: Introductionmentioning

confidence: 99%

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Wyszynski¹,

Hong²,

Lam³

et al. 2016

Hum. Mol. Genet.

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Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERa-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERa binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR ¼ 0.68 95%CI 0.55-0.83, P ¼ 0.0002; replication OR ¼ 0.77 95% CI 0.73-0.82, P ¼ 2.1 Â 10 À19 ) and identify 13 additional linked variants (r 2 > 0.8) in the 20Kb linkage block containing the enCNV (P ¼ 3.2 Â 10 À15 À 5.6 Â 10 À17 ). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.

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IGFBP Ratio Confers Resistance to IGF Targeting and Correlates with Increased Invasion and Poor Outcome in Breast Tumors

Cited by 32 publications

References 27 publications

Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci

Can we unlock the potential of IGF-1R inhibition in cancer therapy?

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

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