This proposed project will test a central hypothesis that aged milieu of the organism has an impact on the pathobiology of prostate cancer. Prostate cancer is one of the human cancer types most notably associated with advanced age. In fact, old age is thought as the most significant risk factor for developing prostate cancer in men. Several aging-associated molecular and cellular changes, such as changes in the prostatic microenvironment (e.g., chronic inflammation, changes in collagen and smooth muscle cells in the stroma), oxidative stress, genomic damage due to androgenic stimulation, changes in the hormone milieu (e.g., estrogen/androgen ratio), and changes in metabolism, etc., may contribute to prostate tumorigenesis. Among somatic mutations in prostate cancers, gene fusions involving ETS family transcription factors (mainly ERG, followed by ETV1) have been found in ~50% of human prostate cancer cases. The majority of these gene fusions are formed by joining the control region of an androgen (and estrogen)-responsive gene, TMPRSS2, to the coding region of ERG or ETV1. Collectively, these ETS fusions represent an early event in prostate tumorigenesis. Several Cre/loxP-based inducible knockin mouse models were generated by us to recapitulate the three major types of TMPRSS2-ETS fusions found in patients, including TMPRSS2-ERG fusion with an interstitial deletion between TMPRSS2 and ERG loci (both genes are located on human chromosome 21 and are ~3Mb apart), TMPRSS2-ERG fusion without deletion, and TMPRSS2-ETV1 fusion. Previous studies using these models showed that while neither of the Tmprss2-ETS fusions alone was sufficient to initiate prostate tumorigenesis, they could all cooperate with Pten-loss to drive prostate cancer progression, suggesting these fusions sensitize prostate cells for cooperation with additional oncogenic events during prostate tumorigenesis. As these findings were made in young mice, it is hypothesized that in aged mice, aging-associated molecular and cellular changes may cooperate with TMPRSS2-ETS fusions, leading to prostate cancer initiation and/or progression. To test this hypothesis, a CreER knockin (to the constitutive Rosa26 locus) mouse model (R26-CreER) will be used to control activation of Tmprss2-ETS knockin alleles, either alone or together with inactivation of one copy of Pten, in prostate cells, by administration of tamoxifen to either aged (24 months) or matched young (4 months) male mice. The induced mice will be followed for up to one year to determine the incidence, kinetics, grade and pathology [e.g., prostatic intraepithelial neoplasia (PIN) or invasive cancer] of prostate lesions. A comparison of these in the aged versus young cohorts would reveal aging-associated changes and whether such changes cooperate with Tmprss2-ETS fusions, or with Tmprss2-ETS fusions plus Pten-loss to drive prostate cancer development, and whether old mice represent a better model for studying prostate cancer.
This proposed project will test the idea that aging-related changes may affect the outcome of human disease, and in this case, prostate cancer, which is clearly associated with old age in men. In particular, the research idea will be tested under the context of prostate cancer with TMPRSS2-ETS gene fusions (ETS: ERG or ETV1 transcription factor), which are mutations frequently found in prostate cancer cells that are by themselves insufficient to initiate prostate cancer development. The proposed experiments will determine whether aging-associated changes cooperate with TMPRSS2-ETS fusions to drive development of prostate cancer, which is essential for understanding how aging affects human cancer development.
|Sandoval, Gabriel J; Pulice, John L; Pakula, Hubert et al. (2018) Binding of TMPRSS2-ERG to BAF Chromatin Remodeling Complexes Mediates Prostate Oncogenesis. Mol Cell 71:554-566.e7|