Ras-related protein 1 and the insulin-like growth factor type I receptor are associated with risk of progression in patients diagnosed with carcinoma in situ.
Currently, there are no applied molecular markers to aid in predicting risk of carcinoma in situ (CIS) progression to invasive cancer, and therefore, all women diagnosed with CIS undergo surgery. Standard assessment of protein expression in fixed tissue by immunohistochemistry (IHC) is not quantitative and hence is not well suited for measuring biomarkers. In this study, we developed an original analytical method for IHC quantification. Using our novel image-based uniplex (IBU) method, quantitative protein profiling was performed on 90 samples of the breast (17 histologically normal tissues, 16 benign lesions, 15 CIS, and 42 invasive carcinomas). Differences between groups were assessed using analysis of variance (ANOVA) and mixed effects models. Measuring protein expression on a continuous scale revealed a significant increase in Ras-related protein 1 (Rap1) and the insulin-like growth factor type I receptor (IGF-IR) in conjunction with the presence of cancer invasion. Women with invasive cancers were four times more likely to have increased levels of Rap1 [odds ratio (OR) = 3.91; P = 0.0002] and IGF-IR (OR=4.33; P<0.0001) than women with non-invasive lesions. Furthermore, expression of both proteins was also increased significantly in CIS adjacent to invasive tumors compared with non-cancerous tissue. These novel findings of a significant up-regulation of Rap1 and IGF-IR in CIS progressing to invasive cancers warrant further investigation of Rap1 and IGF-IR together as a dual biomarker to aid in predicting risk of progression and ultimately providing non-surgical treatment options to those at lower risk.
The Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, University of Pennsylvania, 313 Stemmler Hall, 37th and Hamilton Walk, Philadelphia, PA, 19104, USA. danakf@sas.upenn.edu
Dana K
DK
Furstenau
Nandita
N
Mitra
Fei
F
Wan
Robert
R
Lewis
Michael D
MD
Feldman
Douglas L
DL
Fraker
Marina A
MA
Guvakova
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D002278:Carcinoma in Situ / Q000737:chemistry* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016017:Odds Ratio; D015143:Philadelphia; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000032:analysis*; D018570:Risk Assessment; D012307:Risk Factors; D015854:Up-Regulation; D020668:rap GTP-Binding Proteins / Q000032:analysis*
D014408:Biomarkers, Tumor; D017526:Receptor, IGF Type 1; D020668:rap GTP-Binding Proteins