Expression of Insulin-Like Growth Factor-I Receptor (IGF-IR) in Normal Breast Tissue and Breast Cancer Risk: Results from the Nurses' Health Study
Y Wang, J Connolly, R Hu, H Baer, G Colditz, S Schnitt, L Collins, R Tamimi. Beth Israel Deaconess Medical Center, Boston; Brigham and Women's Hospital, Boston; Harvard School of Public Health, Boston; Harvard Medical School, Boston; Washington University School of Medicine, St. Louis
Background: IGF-IR is a transmembrane tyrosine kinase receptor activated by binding with insulin-like growth factor-I (IGF-I). Prior studies support a role for the IGF-I/IGF-IR pathway in breast cancer development and progression, and elevated serum IGF-I has been associated with an increased breast cancer risk. However, a possible association between IGF-IR expression in normal breast tissue and risk of subsequent breast cancer has not been previously evaluated.
Design: We conducted a case-control study of benign breast disease (BBD) and breast cancer risk nested within the Nurses' Health Study. Tissue microarrays (TMA) containing normal terminal duct lobular units (TDLUs) were constructed from 240 benign breast biopsies with available tissue blocks (59 cases; 181 controls). TMA sections were immunostained for IGF-IR and assessed blinded to case/control status for membrane and cytoplasmic expression in normal TDLUs. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for the association between IGF-IR expression and subsequent breast cancer risk adjusting for age and BBD category.
Results: There was no relationship between membranous expression of IGF-IR in normal TDLU epithelial cells and subsequent breast cancer risk (OR 0.84; 95% CI 0.51-1.38). In contrast, cytoplasmic IGF-IR expression was associated with an almost 2-fold increase in risk for subsequent breast cancer (OR 1.89; 95% CI 1.19-3.01). Among the small subset of women in whom the normal epithelium showed cytoplasmic staining for IGF-IR in the absence of membrane staining, the OR for subsequent breast cancer was 4.26, but the 95% confidence interval was broad (1.41-12.81).
Conclusions: Among women with biopsy-proven BBD, cytoplasmic expression of IGF-IR in normal breast epithelial cells was associated with an almost 2-fold increase in breast cancer risk, independent of BBD category. This finding raises the possibility that blocking IGF-I/IGF-IR signaling may represent a new breast cancer prevention strategy.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 54, Monday Morning