Genetic Modifiers of Intitiation and Progression of Mammary Cancer

迄今为止，已经确定了十种不同的基因与转移性疾病的遗传易感性相关，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一分子途径中起作用。由于转移级联的复杂性，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途径的反复关联表明，它可能在乳腺癌的转移过程中发挥重要作用。我们希望对该通路的进一步表征和研究可能会使我们更深入地了解与转移性疾病相关的潜在过程。然而，尽管这一分子途径趋同，我们实验室的证据表明，肿瘤传播和转移必须有其他途径。人类关联研究质疑我们的转移易感基因在乳腺癌中的作用，已经证明仅在前哨淋巴结中诊断为无肿瘤细胞的患者中存在关联。在原发肿瘤诊断时前哨淋巴结内有肿瘤细胞的患者，在转移易感基因变异与疾病结局之间没有关联。这一结果表明，至少有两种不同的基因定义的乳腺癌转移机制需要研究，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，我们还研究了各种环境暴露对转移性疾病的影响。通过与北卡罗来纳大学和NCSU的研究人员合作，我们证明了高脂肪饮食显著增加了发生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，也可能是由于高脂肪饮食引起的非肿瘤组织的变化。此外，我们与NIH的其他研究人员合作，研究了特定癌症治疗方案对转移扩散的影响，并发现一些证据表明，这种特定治疗可能在某些情况下促进肿瘤转移。

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.