Genetic Regulation of Human Breast Cancer Dormancy

人类乳腺癌休眠的基因调控

• 批准号: 6949698
• 负责人: Nancy Demore
• 金额: $ 13.03万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-16 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6949698
• 关键词: MCF7 cell; angiogenesis; biotechnology; breast neoplasms; cell growth regulation; cell line; clinical research; gene expression; gene induction /repression; gene mutation; genetic mapping; genetic markers; genetic regulation; human tissue; immunocytochemistry; laser capture microdissection; mammary epithelium; metastasis; microarray technology; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic growth; nucleic acid amplification techniques; phenotype; polymerase chain reaction; tissue /cell culture

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.

描述（由申请人提供）：乳腺癌仍然是当今对女性最重要的健康威胁之一。美国癌症协会估计，在美国，1999年因乳腺癌而导致176,300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可检测的临床检测到可检测的转移。肿瘤复发的长期风险已得到充分认识：修复原发性原发性肿瘤后10到20年可能出现转移。乳腺癌患者肿瘤转移的临床研究表明，肿瘤细胞可以在复发期间处于休眠期，然后在复发期间快速生长。因此，休眠的肿瘤种群在数月或数年内一直无法诊断，因此构成了持续复发的风险。控制肿瘤休眠的分子机制仍然未知。但是，我们的实验室最近确定，与淋巴结淋巴结大量迁移酶相比，人类乳腺癌的微转移量降低了增殖和血管生成率，凋亡没有差异。基于这些发现，我们假设微型和大量变体之间的基因表达存在差异，这些基因表达解释了血管生成和增殖的表型差异。因此，直接或间接（抑制基因丧失）的基因激活对于休眠微转移酶的生长是必要的。通过比较微型转移酶和大量变体之间的遗传差异，我们可能能够发现新的基因或新型基因表达模式，这些模式导致靶向转移器官中发生的肿瘤血管生成和增殖。我们建议的具体目的是：1）表征微转移中定义的基因与大宏转移酶，2）内皮细胞中的基因发现和微转移酶，3）候选基因的分子表征。通过比较微型变量和大小变体之间的遗传差异，我们可能会发现靶向转移器官中发生的肿瘤血管生成和增殖的新型基因。这些基因可能是未来治疗策略的药物基因组学靶标。