Genetic Modifiers of Intitiation and Progression of Mammary Cancer

到目前为止，已经确定了10种不同的基因，这些基因与遗传性易患转移性疾病有关，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表明，它们中的许多似乎都在单一的分子途径内发挥作用。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通路的反复关联表明，它可能在乳腺癌的转移过程中发挥重要作用。人们希望，对该途径的进一步表征和研究可能导致对与转移性疾病相关的潜在过程的更深入的了解。然而，尽管这一分子途径趋同，但我们实验室的证据表明，一定存在其他肿瘤扩散和转移的途径。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，已经证明只有在被诊断为前哨淋巴结中没有肿瘤细胞的患者中才有这种关联。被诊断为原发肿瘤的前哨淋巴结内有肿瘤细胞的患者，转移易感基因的变异与疾病结局之间没有相关性。这一结果表明，必须至少有两种不同的乳腺癌转移基因机制需要研究，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，我们还一直在研究各种环境暴露对转移疾病的影响。在与北卡罗来纳大学和国立大学的研究人员的合作下，我们已经证明了高脂肪饮食显着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，而且可能是由于高脂饮食诱导的非肿瘤组织的变化。此外，与其他NIH研究人员合作，我们调查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，在某些情况下，这种特定治疗可能会促进肿瘤转移。

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.