Differential Expression of IR-a, IR-B and IGF-1R in Endometrium Reflects Physiology during the Menstrual Cycle and Demonstrates a Distinct Expression Signature in Endometrial Adenocarcinoma
Presentation Number: PP04-4
Date of Presentation: June 21st, 2014
Clare A Flannery*1, Anne M Rowzee2, Farrah Saleh1, Gina Choe1, Pinar Kodaman1, Teresa L Wood3 and Hugh S Taylor1
1Yale University School of Medicine, New Haven, CT, 2New Jersey Medical School/Rutgers University, Newark, NJ, 3New Jersey Med Sch, Rutgers Biomedical & Health Sciences, Newark, NJ
Women with obesity, PCOS, or Type 2 Diabetes Mellitus are at risk for endometrial hyperplasia and adenocarcinoma. The expression of insulin-like growth factor 1 receptor (IGF-1R) is well-characterized in the endometrium during decidualization and is known to promote cancer growth. The insulin receptor has two splice variants, IR-A and IR-B, which have mitogenic and metabolic roles, respectively; IR-A and IR-B expression are not well characterized in the endometrium. We hypothesized that IR-A and IR-B mRNA expression in endometrial tissue vary differently across the menstrual cycle, suggesting distinct roles in the physiology of normal endometrium. In addition, we hypothesized that the mitogenic receptors IR-A and IGF-1R have higher expression in endometrial adenocarcinoma.
We developed a highly specific quantitative PCR assay to quantify and compare IR-A, IR-B, and IGF-1R expression. We determined receptor expression in endometrial tissue from cycling women using no hormonal medication (n=45, mean age 36+/-1, range 20-48 years) and women with endometrial adenocarcinoma, type 1 (n=10, mean age 58+/-4). Gene expression was normalized to actin, and analyzed for each phase of the menstrual cycle: early proliferative (EP, D1-7), late proliferative (LP, D8-14), early secretory (ES, D15-21), and late secretory (LS, D22-28).
IR-A increased dramatically during the early proliferative phase, with a mean mRNA expression 20 fold-higher than either IR-B or IGF-1R (p=0.002). IGF-1R was at its lowest expression during EP (p<0.03). During LP, IR-B and IGF-1R rose slowly, reaching their individual maximum expressions during ES (p<0.01). In LP and ES phases, the relative ratios of IR-A: IR-B: IGF-1R were 1:1:1, but then altered to 3:2:1 in LS phase due to an increase in IR-A and decrease in IGF1-R expression. In endometrial adenocarcinoma tissue, the mean relative expressions of IR-A: IR-B: IGF-1R were similar (1.5: 1.6: 1; p=NS), and most resembled the levels seen during ES phase. Receptor expression did not vary with either age or body mass index in normal tissue or histological grade in malignant tissue.
The dramatic rise of IR-A corresponds to the rapid increase in endometrial thickness seen during the early proliferative phase, indicating IR-A is likely the predominant isomer responsible for glandular proliferation in normal endometrial physiology. In contrast, IR-B and IGF-1R reached their maximum expressions during the early secretory phase, indicating a role in decidualization involving the differentiation of stromal cells and accumulation of glycogen in epithelial cells. Surprisingly, IR-B was equal in expression to the mitogenic receptors IR-A and IGF-1R in endometrial adenocarcinoma. This is distinct from that reported in prostate, breast, lung, and colon cancer and supports a role for metabolic IR signaling in endometrial adenocarcinoma.
Nothing to Disclose: CAF, AMR, FS, GC, PK, TLW, HST