Genetic Modifiers of Initiation and Progression of Mammary Cancer

自从这个项目开始以来，已经取得了一些进展。首先，通过动物模型，该项目首次证明了遗传易感基因的存在使个体易患转移性疾病。随后，我们证明了这些基因在人类同源物中的多态性也与远端无转移生存相关，证明了这些基因在人类疾病中的重要作用。此外，对人类数据的分析表明，人类乳腺癌转移存在多种易感机制，因为雌激素受体阳性女性乳腺癌易感性的多态性与雌激素受体阴性肿瘤的转移无关，反之亦然。对TCGA数据和乳腺癌易感性数据集的分析表明，在转移易感性筛查中发现的基因与乳腺癌易感性无关，也不经常发生体细胞突变。因此，这些基因代表了一类新的基因，它们与肿瘤细胞和协同肿瘤相关基质通过转移级联进行的效率相关。迄今为止，使用这些方法，我们已经发表了10个转移易感基因和6个转移相关的microrna。另外8个基因已经通过了我们的初步验证研究，手稿要么正在准备中，要么正在接近准备阶段。在接下来的四年里，我们计划通过利用ENCODE项目开创的技术和策略，进一步加速候选基因的发现，继续绘制转移性景观。我们预计这些方法将识别更多的新基因，暗示与转移进展相关的新的分子和细胞机制，并可能为临床预防和/或晚期肿瘤疾病的管理揭示重要的可操作靶点。有趣的是，我们积累的数据开始反复暗示一些分子和细胞系统是转移易感性的主要贡献者。肿瘤自主易感性似乎与粘附连接-细胞骨骼- linc复合物组分显著相关。这些结构将细胞外粘附复合物连接到核膜的内表面，表明检测细胞外微环境信号，机械传递到细胞核，可能在肿瘤进展中发挥重要作用。肿瘤的非自主易感性似乎主要是由免疫系统介导的，特别是细胞介导的反应。进一步的研究正在进行中，以验证和扩展这些观察结果，以便更好地了解这些机制如何促进乳腺癌的进展。最后，我们在小鼠模型中进行的系统遗传学分析开始揭示与转移易感性相关的转录信号，这些信号表明了特定途径的活性。重要的是，许多这些途径已经成为针对其他适应症的药物开发的目标。FDA批准的化合物存在于许多这些途径中，并且可能被证明与当前的辅助治疗标准护理一起用于预防转移。目前正在动物模型系统中验证这些化合物的效用。如果成功，我们预计这些化合物可能会迅速转化为临床由于预先存在的批准。

Since the inception of this project, a number of advances have been made. First and foremost, using animal models, this project was the first to demonstrate that inherited susceptibility genes exist that predispose individuals to the development of metastatic disease. Subsequently, we demonstrated that polymorphisms in the human orthologs of these genes were also associated with distant metastasis-free survival, demonstrating an important role for these genes in human disease. Further, analysis of the human data has shown that multiple susceptibility mechanisms exist for human breast cancer metastasis since polymorphisms that predispose women with estrogen receptor positive breast cancer were not associated with metastasis in estrogen receptor negative tumors and vice versa. Analysis of the TCGA data and breast cancer susceptibility data sets suggest the genes discovered in the metastasis susceptibility screens are not associated with predisposition for breast cancer nor are they frequently somatically mutated. These genes therefore represent a novel class of genes that are associated with efficiency with which tumor cells and the collaborating tumor-associated stroma proceed through the metastatic cascade. To date, using these methods, we have published 10 metastasis susceptibility genes and 6 metastasis-associated microRNAs. Eight additional genes have passed our initial validation studies and manuscripts are either in preparation or are approaching the preparation stage. Over the next four years we plan to continue mapping out the metastatic landscape by exploiting the technologies and strategies pioneered by the ENCODE project to further accelerate candidate gene discovery. We anticipate these methods will identify additional novel genes, implicate new molecular and cellular mechanisms associated with metastatic progression and potentially reveal important actionable targets for clinical prevention and/or management of advanced neoplastic disease. Intriguingly, our accumulating data is beginning to repeatedly implicate a few molecular and cellular systems as major contributors to metastatic susceptibility. Tumor autonomous susceptibility appears to be significantly associated with the adherins junction-cytoskeletal-LINC complex components. These structures, which connect the extracellular adhesion complexes to the inner face of the nuclear membrane, suggest that detection of extracellular microenvironmental cues that are mechanically transmitted to the nucleus may play an important role in tumor progression. Tumor non-autonomous susceptibility appears to be mediated primarily by the immune system, specifically cellular mediated responses. Further investigations are in progress to validate and extend these observations to provide greater understanding of how these mechanisms contribute to breast cancer progression. Finally, the systems genetics analysis in our mouse models is beginning to reveal transcriptional signals associated with metastatic susceptibility that are indicative of specific pathway activities. Importantly, many of these pathways have been targeted for drug development for other indications. FDA approved compounds exist for a number of these pathways, and may prove to be useful for metastasis prevention in conjunction with current adjuvant therapy standard of care. Validation of the utility of these compounds is currently underway in our animal model systems. If successful we anticipate that these compounds might rapidly be translated into the clinic due to pre-existing approval.