The mutations in the Ras genes are among the most widely observed genetic changes during tumorigenesis in humans, including advanced prostate cancer. Metastasis to the bone is one of the most clinically important features of advanced prostate cancer, and understanding the signaling networks that promote bone metastasis is central to developing improved outcomes for patients. Chromosomal rearrangements are common events in human prostate cancer. ETS gene rearrangement seems to be a key event in driving prostate neoplastic development. Loss of heterozygosity of ETV6, a member of ETS family, is observed in prostate cancer and suggests a role for ETV6 as a tumor suppressor. It has been shown that ETV6 plays a critical role in prostate cancer and decreased ETV6 expression was also shown in clinical metastatic prostate cancer. However, the biological function of ETV6 that suppresses metastasis of Ras-activated prostate cancer cells remains unclear. The first aim of this study will investigate the biological functions of ETV6 that suppresses the metastatic potential of Ras-activated prostate cancer cells. ETV6 is a ubiquitously expressed transcription factor with a repressor activity that interacts with the mSin3 and SMRT corepressors to regulate transcription. Few downstream targets have been described in prostate cancer. It is not clear how ETV6 expression related to Ras signaling in prostate cancer metastasis. TWIST1 has been shown to be expressed at high levels in prostate cancer and found to associate with Ras mutation in lung and breast cancer. Our preliminary results found that TWIST1 is one of a candidate target gene for ETV6. Following bioinformatic analysis of clinical gene expression databases, our preliminary results suggest that the expression of decreased ETV6 and increased TWIST1, correlated to Ras mutation prostate cancer progression. The second aim of this study will elucidate the regulatory mechanisms of ETV6 that targets TWIST1 in Ras-activated prostate cancer cells. Most of drug failures in metastatic cancers are attributed to chemoresistance. Understanding the intrinsic molecular mechanisms of resistance to this drug in prostate cancer, especially as related to signaling pathways and ETV6 regulation, is a major objective of our proposed studies. Down-regulation of miR-1 has been described in prostate cancer and overexpression of miR-1 in lung cancers cells contributed to the sensitivity of chemotherapy. We have found a significant increase in mean expression of ETV6 was positively correlated to miR-1 by prostate clinical gene expression databases analysis. However, the role of ETV6 target anti-apoptosis signaling, and how it overexpression contributes to the induction of apoptosis in chemoresistant prostate cancer cells remain largely unknown. The third aim of this study will explore the therapeutic roles of ETV6 that associates with miR-1 and overexpression of ETV6 contributes to sensitivity of chemotherapy in Ras-dependent prostate cancer metastasis. In this four-year research project, we plan to expand on these preliminary results to test a linked role between ETV6 and miR-1 loss and increased TWIST1, and provide evidence to show how ETV6 regulates Ras signaling genes in prostate cancer metastasis and chemoresistance.
|Effective start/end date||8/1/14 → 7/31/15|
- prostate cancer
- bone metastasis
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