Genetic Modifiers of Initiation and Progression of Mammary Cancer

乳腺癌仍然是最常见的恶性肿瘤，是美国妇女癌症相关死亡的第二大原因。据估计，2018年美国有超过266，000例乳腺癌新发病例，其中41，000例患者死于该疾病。虽然对于诊断为局部疾病的患者，5年生存率接近100%，但对于诊断为远处转移性疾病的患者，5年生存率仅为27%，这突出了转移过程在患者死亡率中的至关重要性。对于那些诊断为局部疾病的患者，辅助化疗的广泛应用使晚期复发和长期死亡率降低了约19%。然而，尽管做出了这些努力，25%接受辅助化疗的患者仍进展为转移性疾病。尽管治疗策略发生了变化，但观察到这些患者的生存率几乎没有改善。目前，据估计，美国目前有155，000名妇女患有转移性疾病，突出了这种疾病的重大公共卫生负担。因此，获得对转移灶的病因学和生物学的全面了解以开发更有效的临床干预措施以进一步降低晚期乳腺癌的发病率和死亡率至关重要。在2022财年，我们实施了两种平行策略，以进一步研究乳腺癌转移的病因。第一种策略研究了可能作为转移进展的驱动突变的体细胞突变和拷贝数变异的获得。扩展我们先前在MMTV-PyMT小鼠模型中的分析，我们已经向我们的数据集添加了额外的原发-转移对，以及分析了转移性乳腺癌的三个额外模型，MMTV-Myc，MMTV-Her 2和C3（1）-TAg。令人惊讶的是，与原发性肿瘤转化不同，由单核苷酸变体（SNV）诱导的在转移中富集的激活突变相对罕见，表明点突变不是肿瘤进展的主要驱动因素。相比之下，复发性拷贝数变异（CNV）经常富集转移相比，原发性肿瘤的基因型特异性的方式，这表明基因组的不稳定性可能是主要的体细胞驱动器的转移性疾病。然而，尽管有这些复发性CNV，RNAseq显示匹配的原发性和转移性病变之间几乎没有转录变异。这些数据表明，瞬时相互作用和细胞反应可能是更重要的转移进展比稳定的差异，基因组的不稳定性可能需要使细胞可塑性在多个细胞的侮辱和挑战过程中面临的转移级联。第二个策略是继续我们的遗传学研究转移易感性的病因。在2022财年，我们发表了一项关于核孔蛋白NUP 210在转移性进展中的作用的研究结果。这些研究表明，NUP 210介导从细胞外环境到迁移和侵袭基因的平衡启动子的机械信号传导，诱导肿瘤从原发性肿瘤块传播。有趣的是，蛋白质组学分析表明，其他的，以前确定的，转移易感基因也参与这种机械反应机制。这些独立鉴定的转移相关因子在单个多蛋白复合物上的聚合表明我们的遗传策略正在询问转移级联的关键组成部分。重要的是，这些基因在转移的实验模型系统和人类临床样品中不经常突变。因此，我们的基因易感性筛选似乎突出了传统癌症研究策略难以获得的重要细胞和分子机制。目前的努力集中在更详细的分析机制和潜在的整合额外的转移易感基因，可能有助于肿瘤传播mechanotransductionresponse。

Breast cancer remains the most commonly diagnosed malignancy and is the second leading cause of cancer-related death in American women. It is estimated that there were more than 266,000 new cases of breast cancer in the United States in 2018, with 41,000 patients succumbing to the disease. Although the 5-year survival approaches 100% for those patients diagnosed with localized disease, the 5-year survival rate for patients diagnosed with distant metastatic disease in only 27%, highlighting the critical importance of the metastatic process in patient mortality. For those patients diagnosed with localized disease, the widespread application of adjuvant chemotherapy has reduced late relapse and long-term mortality by an estimated 19%. However, despite these efforts, 25% of patients receiving adjuvant chemotherapy still progress to metastatic disease. Despite changes in therapeutic strategies little improvement in the survival of these patients has been observed . At present it is estimated that 155,000 women are currently living with metastatic disease in the United States, highlighting the significant public health burden of this disease. It is therefore critically important to obtain a comprehensive understanding of the etiology and biology of metastases to develop more effective clinical interventions to further reduce the morbidity and mortality of advanced breast cancer. In FY22 we have performed two parallel strategies for further investigations into the etiology of breast cancer metastasis. The first strategy investigated the acquisition of somatic mutations and copy number variations that might function as driver mutations for metastatic progression. Extending our previous analysis in the MMTV-PyMT mouse model, we have added additional primary-metastasis pairs to our data set, as well as analyzing three additional models of metastatic mammary cancer, MMTV-Myc, MMTV-Her2 and C3(1)-TAg. Surprisingly, unlike the in primary tumor transformation, activation mutations enriched in metastases, induced by single nucleotide variants (SNVs), were relatively rare suggesting that point mutations are not a major driver of tumor progression. In contrast, recurrent copy number variations (CNVs) were frequently enriched metastases compared to primary tumors in a genotype-specific manner, suggesting that genomic instability may be the primary somatic driver of metastatic disease. Despite these recurrent CNVs, however, RNAseq revealed little transcriptional variation between matched primary and metastatic lesions. These data imply that transient interactions and cellular responses may be more important in metastatic progression than the stable differences, and that genomic instability may be required to enable cellular plasticity during the multiple cellular insults and challenges faced during the metastatic cascade. The second strategy pursued is the continuation of our genetic studies into the etiology of metastasis susceptibility. In FY2022 we published the results of a study of the role of the nuclear pore protein, NUP210, in metastatic progression. These studies demonstrated that NUP210 mediates mechanical signaling from the extracellular environment to poised promoters of migration and invasion genes, inducing tumor dissemination from the primary tumor mass. Intriguingly, proteomics analysis has revealed that additional, previously identified, metastasis susceptibility genes also participate in this mechanical response mechanism. The convergence of these independently identified metastasis-associated factors on a single multiprotein complex suggests that our genetic strategy is interrogating a critical component of the metastatic cascade. Importantly, these genes are not frequently mutated in either experimental model systems of metastasis nor in human clinical samples. Thus, our gene susceptibility screen appears to be highlighting important cellular and molecular mechanisms that would be difficult to access by conventional cancer research strategies. Current efforts are focused on more detailed analysis of the mechanisms and potential integration of additional metastasis susceptibility genes that may contribute to the tumor dissemination mechanotransduction response.