Investigating How a Balance of Negative and Positive ETS Factors Controls Prostate Oncogenesis

初步数据：一半的前列腺癌是由基因融合引起的，这种融合使雄激素能够驱动 前列腺细胞中正常沉默的ETS转录因子ERG的表达。最近的基因组景观 对这类癌症的研究报道了ETS中罕见但复发的点突变和狭窄的局灶性缺失 阻遏蛋白ERF。在这里，我们表明这些ERF突变导致蛋白质稳定性降低，并且大多数是 排除ERG融合的患者。ERF损失概括了 正常小鼠前列腺细胞的ERG增益，包括雄激素受体（AR）转录的扩增 ERF在相同的PTEN缺失遗传背景下具有肿瘤抑制活性， ERG的致癌活性。在具有野生型ERF的肿瘤的更常见情况下，ChIP-seq 研究表明，ERG抑制ERF在正常人和正常人的共有ETS位点结合DNA的能力， 前列腺癌细胞与竞争模型一致，ERF过表达阻断了ERG依赖的 肿瘤生长和ERF损失将ERG阳性前列腺癌细胞从ERG依赖性中拯救出来。这 初步数据在申请人的第一作者手稿中描述，该手稿在《自然》杂志上出版。理由和 目的：我们现在已经发现，"阴性" ETS中的功能突变和拷贝数缺失 前列腺癌的症状有哪些？（一）我们的目标是确定消极的集体重要性 前列腺癌中的ETS因子（ETV3和ETV6）突变。II）我们的目标是确定ERF是否为阴性 通过影响AR结合DNA的能力或通过主动抑制其功能来调节AR。（三）我们认为， 即使在正常前列腺中，阴性ETS因子也持续地胜过阳性ETS因子。我们寻求 确定这些内源性的积极ETS因素。影响：这些研究的结果将描述ETS如何 这些因子在正常前列腺细胞内协调。他们也可能阐明为什么TMPRSS2-ERG是一个穷人， 临床生物标志物。第三，它们可以解释一半的前列腺癌的发病机制， TMPRSS2-ERG。最后，他们可能揭示了其他ETS依赖性癌症的肿瘤发生， 如白血病和肉瘤。申请人和职业发展：申请人Rohit Bose博士是 在Charles Sawyers实验室从事博士后工作，同时也是生殖科的讲师 纪念斯隆凯特琳癌症中心（MSKCC）他制定了一个五年职业规划， 他的研究背景是研究前列腺肿瘤发生的分子机制， 接受肿瘤内科学培训。Bose博士将在Charles博士的指导下进行拟议的研究 Sawyers是国际公认的前列腺癌生物学和靶向治疗开发专家， 在培养成功的医学科学家方面有着良好的记录。MSKCC提供理想的机构 环境博士Bose着手拟议的研究计划，并过渡到一个位置，作为一个 拥有自己的实验室和R01基金的独立学术研究者。

Preliminary Data: Half of all prostate cancers are caused by a gene-fusion that enables androgens to drive expression of the normally silent ETS transcription factor ERG in prostate cells. Recent genomic landscape studies of such cancers have reported rare but recurrent point mutations and narrow focal deletions in the ETS repressor ERF. Here we show these ERF mutations cause decreased protein stability and are mostly exclusive from those with ERG fusions. ERF loss recapitulates the morphologic and phenotypic features of ERG gain in normal mouse prostate cells, including expansion of the androgen receptor (AR) transcriptional repertoire, and ERF has tumor suppressor activity in the same genetic background of PTEN loss that yields oncogenic activity by ERG. In the more common situation of a tumor possessing wild-type ERF, ChIP-seq studies indicate that ERG inhibits the ability of ERF to bind DNA at consensus ETS sites in both normal and cancerous prostate cells. Consistent with a competition model, ERF overexpression blocks ERG-dependent tumor growth and ERF loss rescues ERG-positive prostate cancer cells from ERG dependency. This preliminary data is described in the applicant's first author manuscript in press at Nature. Rationale and Aims: We have now discovered that loss of function mutations and copy number deletions in `negative' ETS factors are commonplace in prostate cancer. I) We aim to determine the collective importance of negative ETS factor (ETV3 and ETV6) mutations in prostate cancer. II) We aim to determine whether ERF negative regulates AR by affecting AR's ability to bind DNA or by actively repressing its function. III) We believe that negative ETS factors are continually outcompeting positive ETS factors, even in normal prostate. We seek to identify these endogenous positive ETS factors. Impact: The results of these studies will describe how ETS factors coordinate within normal prostate cells. They may also shed light on why TMPRSS2-ERG is a poor clinical biomarker. Thirdly, they may explain the pathogenesis of the half of prostate cancers that lack TMPRSS2-ERG. And finally, they may shed light on the oncogenesis of other ETS-dependent cancers such as leukemias and sarcomas. Applicant and career development: The applicant, Dr. Rohit Bose, is performing his postdoctoral work in Charles Sawyers laboratory and is also an Instructor in the Genitourinary Service at Memorial Sloan Kettering Cancer Center (MSKCC). He has outlined a 5-year career plan that builds upon his research background studying molecular mechanisms of prostate oncogenesis and his clinical training in medical oncology. Dr. Bose will conduct the proposed research under the mentorship of Dr. Charles Sawyers, an internationally recognized expert in prostate cancer biology and targeted therapy development, with a strong track record of training successful physician scientists. MSKCC provides the ideal institutional environment for Dr. Bose to embark on the proposed research program and transition to a position as an independent academic investigator with his own laboratory and R01 funding.