Genetic Regulation of Human Breast Cancer Dormancy

描述（由申请人提供）：乳腺癌仍然是当今女性最严重的健康威胁之一。美国癌症协会估计，1999年美国有176，300例乳腺癌病例和43，700例死亡。乳腺癌患者死亡的主要原因是肿瘤转移，但只有少数患者在诊断时表现出临床可检测的转移。肿瘤复发的长期风险是公认的：即使在原发性肿瘤根治性切除后10至20年，也可能出现转移。乳腺癌患者肿瘤转移的临床研究表明，肿瘤细胞可以经历一段休眠期，然后在复发期间快速生长。因此，休眠的肿瘤群体在临床上保持数月或数年不可检测，因此造成持续的复发风险。控制肿瘤休眠的分子机制仍不清楚。然而，我们的实验室最近已经确定，人乳腺癌微转移的增殖和血管生成率下降，细胞凋亡没有差异，相比淋巴结大转移。基于这些发现，我们推测微转移和大转移之间存在基因表达差异，这是血管生成和增殖的表型差异的原因。因此，直接或间接增加肿瘤细胞生长和血管生成的基因的激活（抑制基因的丢失）对于休眠微转移的生长是必需的。通过比较微转移和大转移之间的遗传差异，我们可能能够发现新的基因或新的基因表达模式，负责肿瘤血管生成和增殖发生在靶转移器官。我们的建议的具体目标是：1）在微转移与大转移中表征定义的基因，2）在内皮细胞和微转移中的基因发现，3）候选基因的分子表征。通过比较微转移和大转移之间的遗传差异，我们可能会发现负责靶转移器官中发生的肿瘤血管生成和增殖的新基因。这些基因可能是未来治疗策略的药物基因组学靶点。

DESCRIPTION (provided by applicant): Breast cancer remains one of the most significant health threats to women today. The American Cancer Society estimated that in the United States there were 176,300 cases and 43,700 deaths due to breast cancer in 1999. The major cause of mortality in breast cancer patients is tumor metastases, but only a minority of patients exhibit clinically detectable metastases at diagnosis. The long-term risk of tumor recurrence is well recognized: metastases may appear even 10 to 20 years after curative primary tumor removal. Clinical studies of tumor metastasis in breast cancer patients show that tumor cells can undergo a period of dormancy followed by rapid growth during relapse. Thus, a dormant tumor population remains clinically undetectable for months or years and consequently poses a continuous risk of recurrence. The molecular mechanisms controlling tumor dormancy remain unknown. However, our laboratory has recently established that human breast cancer micrometastases have decreased rates of proliferation and angiogenesis, with no difference in apoptosis, when compared to lymph node macrometastases. Based on these findings we hypothesize that there are differences in gene expression between micro- and macrometastases that account for the phenotypic differences in angiogenesis and proliferation. Therefore activation of genes that increase tumor cell growth and angiogenesis directly or indirectly (loss of suppressor genes) are necessary for the growth of dormant micrometastases. By comparing genetic differences between micrometastases and macrometastases, we may be able to discover new genes or novel gene expression patterns that are responsible for tumor angiogenesis and proliferation that occur in the target metastatic organ. The specific aims of our proposal are: 1) to characterize defined genes in micrometastases versus macrometastases, 2) gene discovery in endothelial cells and micrometastases, 3) molecular characterization of candidate genes. By comparing genetic differences between micro- and macrometastases, we may discover novel genes that are responsible for tumor angiogenesis and proliferation that occur in the target metastatic organ. These genes could be pharmacogenomic targets for future treatment strategies.