IMP3 is a novel biomarker for triple negative invasive mammary carcinoma associated with a more aggressive phenotype

Department of Pathology, UMass Memorial Medical Center, Worcester, MA, 01655, USA.
Human pathology (Impact Factor: 2.77). 08/2009; 40(11):1528-33. DOI: 10.1016/j.humpath.2009.05.005
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IMP3, an oncofetal protein, is a member of the insulin-like growth factor-II (IGF-II) mRNA-binding protein family. Its relevance as a novel biomarker in lung, pancreatic, renal, and cervical adenocarcinoma was recently revealed. However, its role in breast carcinogenesis and tumor progression is not yet established. Basal-like carcinoma was initially identified by gene expression profiling. It accounts for 15% to 30% of all breast cancers. These tumors express basal epithelial markers including cytokeratin 5 but lack expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), therefore, are often referred to as triple negative breast cancer. They have been found to be associated with a worse overall and disease-free survival. In this retrospective study, we examined the IMP3 expression in invasive ductal carcinoma of the breast and correlated its expression with morphological and biologic prognostic factors. The study group comprised 138 cases of invasive ductal carcinoma retrieved from the surgical pathologic files for a 10-year period from 1997 to 2006. Survival data and clinical stage were available on all 138 patients. Tumor characteristics including size, grade, lymphovascular invasion, necrosis, lymph node metastasis, estrogen receptor, progesterone receptor, and HER2 status were obtained from pathologic reports. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue using mouse monoclonal antibody against IMP3 and CK5/6. Of the 138 breast cancer cases, IMP3 expression was seen in 45 (33%). Twenty-five of the IMP3+ cases were triple negative. We found significant correlation between IMP3 expression and higher grade (P = .001), necrosis (P< .0001) triple negative, and CK5/6 expression (P < .0001 for each). Cox multivariate analysis showed a hazard ratio of IMP3 expression at 3.14 (P = .05). IMP3 is a novel biomarker for triple negative (basal-like) invasive mammary carcinoma, and its expression is associated with a more aggressive phenotype and decreased overall survival.

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Available from: Otto Walter, Jul 13, 2015
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    • "Similar to these previous studies , most specimens (67.92 %) were diagnosed as positive in present results, and expression of IMP3 was significantly higher in specimens with vascular invasion, perineural invasion , nodal metastasis and higher depth of invasion. IMP3 is a immunohistochemical biomarker for detecting a particularly aggressive subtype of breast cancer (triple negative ) that is negative for HER2 and refractory to anti-HER2 therapy (Walter et al. 2009; Won et al. 2013). Studies about the association between HER2 and IMP3 expression have not been described yet in gastric cancer. "
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    ABSTRACT: Background: The aim of this study was to evaluate the expression of IMP3, an independent poor prognostic factor for many cancers, and its association with clinicopathological features and HER2 status. Methods: Gastrectomy specimens from 106 patients were evaluated by immunohistochemistry and fluorescence in situ hybridization. Results: HER2 overexpression was found in 4.71 % of the samples. A negative association was observed between HER2 overexpression and grade of differentiation. No association was observed between HER2 overexpression and status of surgical margins, vascular invasion, perineural invasion, nodal metastasis and depth of invasion. Among all specimens of gastric cancer, 67.92 % were positive for IMP3. Expression of IMP3 was significantly higher in specimens with vascular invasion, perineural invasion, nodal metastasis and higher depth of invasion. HER2 overexpression was detected in only 5.55 % of IMP3 positive specimens. Conclusions: IMP3 expression was frequently observed in gastric cancer and was associated with poor prognostic clinicopathological features. A survival benefit with HER2 therapy should be expected for the minority of patients with IMP3 positive specimens. Studies should be conducted to evaluate the response to HER2 therapy of gastric cancer expressing IMP3.
    Journal of Cancer Research and Clinical Oncology 10/2014; 140(12). DOI:10.1007/s00432-014-1850-9 · 3.08 Impact Factor
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    • "IMP3 expression also seems to correlate with aggressive histological subtypes in urothelial carcinomas [28], breast carcinomas [29], endometrial carcinomas [30] [31] and neuroendocrine tumors of the lung [32]. "
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    ABSTRACT: Aim: Expression of the oncofetal protein insulin like growth factor II messenger ribonucleic acid binding protein 3 (IMP3) has been shown to differentiate between benign and malignant lesions in several tissues. Our aim was to assess the immunohistochemical expression of IMP3 in inflammatory and neoplastic lesions of the gastric mucosa and to determine whether IMP3, alone or in combination with p53, could be used for identifying neoplasia of the gastric mucosa. Methods: IMP3 and p53 immunohistochemistry was performed on 57 cases of gastritis, 28 cases of dysplasia of the gastric mucosa and 63 cases of gastric carcinomas. Focal IMP3 positivity was detected in 86% of non-neoplastic lesions of the gastric mucosa. Using a simple product score (PS), 96% of non-neoplastic lesions of the gastric mucosa were assessed as IMP3(PS) negative. None of the low-grade dysplasia but 83% of high-grade dysplasia were IMP3(PS) positive. Gastric carcinomas showed IMP3(PS) positivity in 65%. Adding p53 to the diagnostic panel increased sensitivity significantly. Conclusion: High-grade dysplasia and gastric carcinomas can be distinguished from low-grade dysplasia and inflammatory lesions of the gastric mucosa with a high specificity and good sensitivity using a combination of the immunohistochemical markers IMP3 and p53.
    International journal of clinical and experimental pathology 05/2014; 7(5):2091-101. · 1.89 Impact Factor
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    • "RESULTS IMP3 and HMGA2 mRNA Are Coexpressed in Human Cancers High levels of RNA-binding IMP3 have been associated with poor outcome and metastasis in cancers of the lung, kidney, colorectal, breast, and ovary (Beljan Perak et al., 2012; Bellezza et al., 2009; Findeis-Hosey et al., 2010; Hoffmann et al., 2008; Jiang et al., 2008a, 2008b; Kö bel et al., 2009; Lochhead et al., 2012; Walter et al., 2009; Yuan et al., 2009). To identify putative oncogenic mechanisms connected to IMP3, we examined IMP3 mRNA expression in a series of 270 tumors from the above cancers and searched for transcripts that were correlated with the presence of IMP3. "
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    ABSTRACT: The IMP3 RNA-binding protein is associated with metastasis and poor outcome in human cancer. Using solid cancer transcriptome data, we found that IMP3 correlates with HMGA2 mRNA expression. Cytoplasmic IMP3 granules contain HMGA2, and IMP3 dose-dependently increases HMGA2 mRNA. HMGA2 is regulated by let-7, and let-7 antagomiRs make HMGA2 refractory to IMP3. Removal of let-7 target sites eliminates IMP3-dependent stabilization, and IMP3-containing bodies are depleted of Ago1-4 and miRNAs. The relationship between Hmga2 mRNA and IMPs also exists in the developing limb bud, where IMP1-deficient embryos show dose-dependent Hmga2 mRNA downregulation. Finally, IMP3 ribonucleoproteins (RNPs) contain other let-7 target mRNAs, including LIN28B, and a global gene set enrichment analysis demonstrates that miRNA-regulated transcripts in general are upregulated following IMP3 induction. We conclude that IMP3 RNPs may function as cytoplasmic safe houses and prevent miRNA-directed mRNA decay of oncogenes during tumor progression.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.03.015 · 8.36 Impact Factor
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