Genetic Modifiers of Initiation and Progression of Mammary Cancer

自该项目开始以来，已经取得了一些进展。首先，也是最重要的是，利用动物模型，该项目首次证明了遗传易感基因的存在，使个人容易患上转移性疾病。随后，我们证明了这些基因的人类同源基因的多态也与无远处转移生存期相关，显示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，因为倾向于雌激素受体阳性乳腺癌女性的多态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的易感性无关，也没有频繁的体细胞突变。因此，这些基因代表了一类新的基因，它们与肿瘤细胞和协作的肿瘤相关间质在转移级联中进行的效率有关。到目前为止，利用这些方法，我们已经发表了10个转移易感基因和6个转移相关microRNAs。另外八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来进一步加快候选基因的发现，从而继续绘制转移的图景。我们预计这些方法将识别更多的新基因，涉及与转移进展相关的新的分子和细胞机制，并可能揭示临床预防和/或治疗晚期肿瘤疾病的重要可操作靶点。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。肿瘤的自主易感性似乎与粘附素连接-细胞骨架-LINC复合体成分显著相关。这些连接细胞外黏附复合体和核膜内表面的结构表明，检测机械传递到细胞核的细胞外微环境信号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由免疫系统介导，特别是细胞介导的反应。进一步的研究正在进行中，以验证和扩大这些观察结果，以更好地了解这些机制如何促进乳腺癌的进展。最后，我们的小鼠模型中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，这些信号表明特定的途径活动。重要的是，这些途径中的许多已经成为药物开发的目标，用于其他适应症。FDA批准的化合物适用于这些途径中的许多，并可能被证明与目前的辅助治疗标准一起用于预防转移。这些化合物的效用目前正在我们的动物模型系统中进行验证。如果成功，我们预计，由于预先存在的批准，这些化合物可能会迅速转化为临床。

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.