Project Details
Description
One of the main challenges in the diagnosis and treatment of prostate cancer (PCa) remains to discriminate indolent PCa which do not require treatment, from lethal aggressive PCa. Elucidating molecular pathways governing early events leading to cancer initiation is an essential step to identify such patients and provide new opportunities for early detection and treatment. Nevertheless, investigations on early stages of human cancers have been limited by the lack of experimental models and the inaccessibility of relevant clinical specimens.Here, we propose to use biologically-relevant mouse models and state-of-the-art technologies in combination with validation to human PCa to elucidate molecular events that govern early stages of prostate cancer. Specifically, we will focus on Nkx3.1 homeobox gene, a key regulator of prostate epithelial differentiation and specification, whose loss of function is one of the earliest events occurring in PCa initiation. Thus, Nkx3.1 appears to represent a candidate of choice to explore mechanisms underlying cancer initiation as a result of normal development deregulation. The present study is based on the hypothesis that the molecular processes by which Nkx3.1 controls prostate epithelial differentiation are causally linked to its role in cancer initiation, while its consequences for malignancy are limited by cellular senescence.In Aim 1, we will investigate the mechanisms governing cellular senescence consequently to Nkx3.1 loss and their consequences for blocking PCa progression. Based on the observation that Nkx3.1 mutant mice display senescence coincident with the occurrence of PIN (Preliminary Data), we will investigate the relationship of the senescence phenotype to cell type, and prostate stem cells. We will evaluate the functions of senescence modulators in renal graft assays and validate their relevance to human prostate cancer.In Aim 2, based on the finding that gain-of-function of Nkx3.1 in non-prostatic epithelium is sufficient to induce prostate growth in vivo (Preliminary Data), we will investigate the mechanisms by which Nkx3.1 induces prostate specification and their relationship to cancer initiation. To do so, we will use gene expression profiling followed by functional analyses of selected genes, and validation to human prostate cancer The proposed study provides a paradigm to understand relationship between normal development and oncogenesis and addresses issues of crucial significance for various cancers.
Status | Finished |
---|---|
Effective start/end date | 2/1/13 → 1/31/14 |
ASJC Scopus Subject Areas
- Cancer Research
- Oncology