Our data indicate that the human prostate-derived Ets transcription factor (PDEF) plays an essential role in tumor suppression via downregulation of the expression of antiapoptotic protein survivin. Ectopic expression of PDEF in PDEF-negative breast cancer cells inhibits survivin expression as well as its promoter activity. In contrast, knockdown of PDEF in PDEF-positive breast cancer cells upregulates survivin expression along with increased cell proliferation in vitro, and increases xenograft tumor take rate and tumor growth in vivo. Importantly, patients with survivin-/PDEF+ tumor show better survival and less relapse than patients with survivin+/PDEF- tumor. Abnormal inhibition of apoptosis is known to be one of the critical steps for oncogenesis and malignant progression. Although the underlying mechanisms are not fully understood, evidence indicates that survivin plays an important role in the initiation, progression, metastasis and recurrence of cancer. Accordingly, many natural dietary components, including resveratrol, silibinin, sulindac, retinoid, selenium and vitamin D compounds that have cancer-preventive and therapeutic effects, downregulate survivin expression. PDEF appears to have an opposing role to survivin and likely via downregulation of survivin expression. It has been shown that PDEF inhibits cancer cell migration, invasion and growth. Based on these observations, we hypothesize that application of survivin and PDEF as interconnected biomarkers and targets to stratify patents with survivin+/PDEF- tumor and patients with survivin-/PDEF+ tumor may facilitate prostate cancer prognosis and personalized medicine.
Two specific aims are proposed to test this hypothesis: 1) determine survivin and PDEF expression status and their association with patient survival, cancer metastasis and tumor relapse using prostate cancer tissues;and 2) determine methylation status of the PDEF gene in prostate cancer tissues and its association with the expression of PDEF and survivin. These studies may provide novel approaches for cancer prognosis and personalized medicine, by considering survivin and PDEF as interconnected biomarkers and targets.
The studies proposed in this project may result in novel cancer prognosis and personalized medicine for clinical applications by considering PDEF and survivin as interconnected biomarkers and targets to stratify patients with PDEF-/survivin+ tumor and patients with PDEF+/survivin- tumor. Additionally, the developed SPlucTg-relevant mouse models may also be very useful for rapid in vivo screening of antitumor compounds that blocks survivin expression and for in vivo-testing drug toxicity and efficacy at the same time.
