Abstract P5-08-05: The influence of doxorubicin on PTEN and PI3K-Akt-mTOR signaling in human breast cancer

Abstract

Abstract Background: De novo as well as acquired resistance are common features of anthracycline therapy in breast cancer. The PTEN tumor suppressor gene is frequently inactivated in human breast cancer, leading to induction of PI3K-Akt-mTOR signaling, which facilitates cell growth, survival, invasion and ultimately tumor progression. Upregulation of the PI3K-Akt-mTOR pathway has been suggested as a possible mechanism of anthracycline resistance, but there is limited data in the clinical setting, including its influence on PTEN expression. Methods: The early PTEN response to doxorubicin was assessed in vitro in MCF7 (estrogen receptor positive) and MDA-MB231 (triple negative) human breast cancer cell lines 24 hours after the initiation of chemotherapy. Tumor samples from thirty patients with locally advanced breast cancer were analyzed for PTEN expression levels and PI3K-Akt-mTOR signaling before and after neoadjuvant anthracycline therapy. The early effect of anthracyclines on PTEN expression is currently being evaluated in human breast cancer samples 24 hours after the initiation of chemotherapy. Mice bearing MCF7 and MDA-MB231 xenografts will be used to assess the potential of PI3K-Akt-mTOR signal transduction inhibitors in preventing anthracycline resistance. Results: PTEN expression was found to be profoundly downregulated in both MCF7 and MDA-MB231 cell lines, 24 hours after exposure to doxorubicin at their respective IC50. An increase in Akt1 protein levels in both cell lines was observed in the same setting. In 19 out of 30 human breast cancers PTEN levels increased after a median of 16 weeks neoadjuvant doxorubicin treatment. No difference between estrogen receptor positive and negative breast cancers was observed. The increase in PTEN was accompanied by an increase in fibrotic tissue in the tumor interior. There was no correlation between PTEN level or treatment-induced alterations in PTEN expression and response rates or recurrence-free survival (RFS). The results from our currently ongoing experiments will be presented. Conclusion: PTEN expression increases in the majority of human breast cancers during long-term exposure to doxorubicin. However, PTEN is greatly downregulated, with corresponding Akt1 increase, 24 hours after exposure to high doses of doxorubicin in vitro. These results indicate different effects of short- and long-term exposure to doxorubicin, which may be of importance to the development of anthracycline resistance, and to understand at what time a combinational approach with inhibitors of the PI3K-Akt-mTOR pathway will be beneficial. Current efforts are aimed at evaluating the potential of such inhibitors to counteract doxorubicin resistance in this setting. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-05.