Genetic Modifiers of Intitiation and Progression of Mammary Cancer

乳腺癌发生和进展的基因修饰因素

• 批准号: 8157732
• 负责人: KENT William HUNTER
• 金额: $ 136.02万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157732
• 关键词: Genetic; Mammary Neoplasms

To date ten different genes have been identified that are associated with inherited predisposition to metastatic disease, with evidence in both mouse model tumor systems and human patient populations. Unexpected, due to the complexity of the metastatic process, further analysis into the mechanistic basis of these genes has revealed that many of them appear to be functioning within a single molecular pathway. Due to the complexity of the metastatic cascade, which requires many different interactions and steps, it was anticipated that little overlap between mechanisms would be observed for most of the genes. The repeated association of the metastasis susceptibility genes with this single molecular pathway suggests that it may play a major role in the metastatic process in breast cancer. It is hoped that further characterization and investigation into the pathway may lead to greater insights into the underlying processes associated with metastatic disease. However, despite the convergence on this molecular pathway, evidence from our laboratory suggests that there must be additional pathways for tumor dissemination and metastasis. Human association studies interrogating the role of our metastasis susceptibility genes in breast cancer has demonstrated an association only in patients diagnosed without tumor cells in their sentinel lymph nodes. Patients who had tumor cells within the sentinel lymph nodes at diagnosis of the primary tumor showed no association between variants in the metastasis susceptibility genes and disease outcome. This result suggests that there must be at least two different genetically defined mechanisms for breast cancer metastasis that need to be investigated to fully understand tumor dissemination and metastasis. In addition to studying the intrinsic factors associated with metastasis, we have been investigating the effects of various environmental exposures on metastatic disease. In collaboration with investigators at UNC and NCSU we have demonstrated that high fat diet significantly increases the probability of developing metastatic disease. The increase in metastatic disease can be ascribed to changes in gene expression and cellular biology of not only the tumor cells themselves, but are also probably due to changes in non-tumor tissues induced by high fat diets. Furthermore, in collaboration other NIH investigators we have investigated the effect of specific cancer treatment regimens on metastatic spread and found some evidence that this specific treatment may in some cases promote tumor metastasis.

迄今为止，已经鉴定出与转移性疾病的遗传易感性相关的十种不同基因，在小鼠模型肿瘤系统和人类患者群体中都有证据。出乎意料的是，由于转移过程的复杂性，对这些基因的机制基础的进一步分析显示，它们中的许多似乎在单个分子途径内起作用。由于转移级联反应的复杂性，需要许多不同的相互作用和步骤，预计大多数基因的机制之间几乎没有重叠。转移易感基因与这一单一分子通路的重复关联表明，它可能在乳腺癌的转移过程中发挥重要作用。希望对该途径的进一步表征和研究可能会导致对与转移性疾病相关的潜在过程的更深入了解。 然而，尽管在这一分子途径上存在共识，但我们实验室的证据表明，肿瘤播散和转移必须有其他途径。人类关联研究询问我们的转移易感基因在乳腺癌中的作用，已经证明了只有在前哨淋巴结中没有肿瘤细胞的患者中才有关联。在前哨淋巴结内有肿瘤细胞的患者在原发性肿瘤的诊断显示转移易感基因的变异和疾病结果之间没有关联。这一结果表明，乳腺癌转移必须至少有两种不同的遗传学定义的机制，需要进行研究，以充分了解肿瘤的传播和转移。除了研究与转移相关的内在因素外，我们一直在研究各种环境暴露对转移性疾病的影响。在与研究人员合作，在马里兰大学和NCSU，我们已经证明，高脂肪饮食显着增加发展转移性疾病的可能性。转移性疾病的增加不仅可以归因于肿瘤细胞本身的基因表达和细胞生物学的变化，而且还可能归因于高脂肪饮食诱导的非肿瘤组织的变化。此外，在其他NIH研究人员的合作下，我们研究了特定癌症治疗方案对转移扩散的影响，并发现了一些证据表明这种特定治疗在某些情况下可能促进肿瘤转移。