Abstract A3: mTOR signaling and tamoxifen response in postmenopausal breast cancer

Abstract

Abstract mTOR is a central, frequently altered, node for the complex growth signaling in breast cancer. Activation of the PI3K/Akt/mTOR-pathway seems to be one of the mechanisms for patients recurring after adjuvant endocrine treatment. Growth factor signals promote phosphorylation of the estrogen receptor alpha (ER), thereby altering the receptor conformation, stability and its response to tamoxifen treatment. Ongoing studies are investigating the possibility to inhibit the mTOR pathway in addition to endocrine treatment or after endocrine treatment failure. In the present retrospective study, a postmenopausal early breast cancer cohort of 812 patients, randomized to tamoxifen or no endocrine treatment, was analyzed according to the protein expression of mTOR phosphorylated on serine 2448. Downstream targets of mTOR are the S6Kinases, S6K1 and S6K2. S6K1 is thought to directly phosphorylate the ER on serine 167. Here, a positive correlation between p-mTOR and p-ERs167 was shown. However, no correlation was detected between p-mTOR and p-ERs305, indicating that the active mTOR signaling specifically targets the ERs167 residue. Activated 4EBP1, another common mTOR target, did not correlate with the p-mTOR protein expression. No prognostic value, independently of cut-off, was seen for p-mTOR expression in this material. Analyses of p-mTOR as a tool for treatment prediction showed that negative, low and medium expression in the tumor did not affect the patients response to tamoxifen, p=0.0001. High and abundant expression decreased the tamoxifen sensitivity to a non-significant degree, p=0.34. An ER-positive/PgR-positive selection further improved the hypothesis of p-mTOR being an indicator of tamoxifen resistance. Where the p-mTOR negative group responded well to treatment (p<0.00001), compared with the p-mTOR positive group, where the treated group did not separate significantly from the controls (p=0.71). In conclusion, the results indicate that risk of recurrence after tamoxifen treatment may increase in patients with high mTOR kinase activity.