The IGF-1R/mTOR Pathway Is Differentially Activated in Tamoxifen Associated High Grade Uterine Tumors
R Buell-Gutbrod, A Tergas, S Yamada, A Fefferman, A Montag, K Gwin. University of Chicago, Chicago
Background: Tamoxifen, a frequently used adjuvant therapy for breast cancer, has an estrogenic effect on the endometrium and a known association with low-grade endometrial cancers. Over the past years however, an increased number of high-grade uterine tumors arising from atrophic endometrium have been reported in patients with a history of tamoxifen use. The kinase mammalian target of rapamycin (mTOR) and its phosphorylated form phospho-mTOR (p-mTOR) are part of a molecular cascade linked to regulation of cell growth, and its activation has been demonstrated in multiple human cancers. Tamoxifen has been shown to interact with estrogen receptors in the endometrium to induce insulin like growth factor signaling via IGF-1R which is an upstream regulator of the P13K/AKT/mTOR pathway. In this study, we compared expression of ER, IGF-1R, mTOR and p-mTOR in patients with tamoxifen exposure and matched controls.
Design: Tissue microarrays were designed from paraffin embedded material of 14 high grade uterine cancers (8 MMMT, 4 serous, 1 endometrioid) of patients previously treated with tamoxifen for breast cancer, and histologic type, grade, age and stage matched controls group (n=27). Expression and localization of ER, IGF-1R, mTOR and p-mTOR were evaluated by IHC.
Results: Strong cytoplasmic staining for IGF-1R was observed in the tamoxifen treated group, with significantly less staining in the control group (p < .01). mTOR/p-mTOR both displayed strong staining in 43% of the tamoxifen cases and in 19/15% of the control group, respectively. Estrogen receptor expression varied among the cases; 64% of the tamoxifen group and 55% of the control group showing no or weak staining, and 28%/22% showing strong nuclear staining. The difference in ER expression of both groups was not statistically significant.
Conclusions: Our results show that IGF-1R is significantly upregulated in the tamoxifen group, indicating the upstream activation of the Akt/mTOR/4E-BP1 pathway in high grade uterine tumors developing after tamoxifen therapy. Expression of mTOR and p-mTOR was increased in the Tamoxifen group compared to the matched control group. No significant difference in the ER status between the tamoxifen group and matched controls was found in this study. Upregulation of IGF-1R and mTOR is of clinical interest as both are potential therapeutic targets.
Category: Gynecologic & Obstetrics
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 149, Monday Morning