Targeting Signal Transducers and Activators of Transcription-3 (Stat3) As a Novel Strategy In Sensitizing Breast Cancer To Egfr-Targeted Therapy
Annual rept. 1 Jun 2007-31 May 2008
DUKE UNIV DURHAM NC
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We have performed proposed studies to test the hypothesis that deregulated EGFR and STAT3 pathways synergistically contribute to the malignant biology of breast cancer and that combined uses of anti-EGFR and anti-STAT3 treatments result in significantly increased breast cancer cell death compared to single agent treatments. Analysis of a panel of human breast cancer cell lines and primary breast carcinoma specimens revealed that EGFR and constitutively activated STAT3 p-STAT3 are frequent and concurrent. EGFR and STAT3 cooperate to induce epithelial mesenchymal transition by activating expression of TWIST, an E-cadherin repressor. In breast cancer cells with high levels of EGFR and p-STAT3, forced expression of dominant-negative STAT3 significantly suppresses cell proliferation. Importantly, dominant-negative STAT3 sensitizes breast cancer cells with high EGFRp-STAT3 to anti-EGFR agent, Iressa. In contrast, transfection of constitutively active STAT3 into these cells does not increase cell proliferation nor induces resistance to Iressa, suggesting the endogenous p-STAT3 is sufficient in facilitating cell survival. Consistently, breast cancer cells with no or low EGFR expression do not respond to Iressa treatments. Together, the findings to date point to significant in vivo and in vitro interactions between EGFR and STAT3 oncoproteins in breast cancer as well as a role of STAT3 constitutive activation may play in the resistance of these tumors to anti-EGFR therapy.
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