Bone derived IGFs in bone metastasis of human breast cancer

骨源性 IGF 在人乳腺癌骨转移中的作用

• 批准号: 6314027
• 负责人: TOSHIYUKI YONEDA
• 金额: $ 18.15万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-09 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6314027
• 关键词: antisense nucleic acid; athymic mouse; bone neoplasms; breast neoplasms; cell proliferation; disease /disorder model; female; growth factor receptors; histopathology; insulinlike growth factor; metastasis; neutralizing antibody; nuclear factor kappa beta; physiologic bone resorption; receptor expression

Breast cancer is the most common malignancy in US women. Approximately 90 percent of patients dying with breast cancer have skeletal metastases. These mestastatic lesions cause devastating complications including intractable bone pain, pathological fractures and hypercalcemia. Thus, bone metastasis is one the major cause of increased morbidity and eventually mortality in breast cancer patients. Nevertheless, the mechanisms by which breast cancer colonizes the skeleton are still poorly understood. Bone stores a variety of growth factors that are released into the bone microenvironment as a consequence of bone resorption. Insulin-like growth factors (IGFs) are the most abundant of the growth factors that are present in bone. Several clinical studies have demonstrated that IGF type I receptor (IGFIR) expression is elevated in malignant breast tumors compared with that in normal breast tissue, and many workers have shown that IGFs stimulate proliferation of cultured human breast cancer cells. We have, therefore, developed a hypothesis that bone-derived IGFs are responsible, at least in major part, for stimulating human breast cancer cell proliferation in the bone microenvironment. An additional goal is to study for the IGFIR downstream signaling pathways which may play a role in bone metastasis of breast cancer. We will focus on the transcription factor NF-kappaB, since it has been shown that IGF-I activates the NF-kappaB and constitutive activation of NF-kappaB has been found to be associated with the progression of metastatic growth of human breast cancer cells. Our Specific Aims are 1. to determine if IGFs released from bone during increased bone resorption accelerates local bone metastasis and proliferation of human breast cancer cells in bone using neutralizing antibodies to IGFIR 2. to examine the effects of stable overexpression of the wild-type IGFIR on the capacity of human breast cancer cells to cause bone metastases 3. to determine the capacity of human breast cancer cells stably overexpressing mutated dominant-negative IGFIR to develop bone metastases 4. to study the role of NF-kappaB in bone metastasis using mutant forms of Ikappa-B which inhibits NF-kappaB activation 5. to examine the effects of antisense oligodeoxynucleotides (ODN) to IGFIR and NF-kappaB on bone metastasis

乳腺癌是美国女性最常见的恶性肿瘤。大约 90% 死于乳腺癌的患者有骨骼转移。 这些转移性病变会导致毁灭性的并发症，包括顽固性骨痛、病理性骨折和高钙血症。 因此，骨转移是乳腺癌患者发病率和最终死亡率增加的主要原因之一。 然而，人们对乳腺癌在骨骼中定植的机制仍知之甚少。 骨骼储存了多种生长因子，这些生长因子因骨吸收而释放到骨骼微环境中。 胰岛素样生长因子（IGF）是骨骼中最丰富的生长因子。多项临床研究表明，与正常乳腺组织相比，恶性乳腺肿瘤中IGF I型受体（IGFIR）的表达升高，并且许多工作人员表明IGF刺激培养的人乳腺癌细胞的增殖。 因此，我们提出了一个假设，即骨源性 IGF 至少在很大程度上负责刺激骨微环境中的人类乳腺癌细胞增殖。 另一个目标是研究可能在乳腺癌骨转移中发挥作用的 IGFIR 下游信号通路。 我们将重点关注转录因子 NF-kappaB，因为已表明 IGF-I 激活 NF-kappaB，并且发现 NF-kappaB 的组成型激活与人乳腺癌细胞转移性生长的进展相关。 我们的具体目标是 1. 使用 IGFIR 中和抗体确定在骨吸收增加期间从骨中释放的 IGF 是否会加速局部骨转移和人乳腺癌细胞在骨中的增殖 2. 检查野生型 IGFIR 的稳定过表达对人乳腺癌细胞引起骨转移的能力的影响 3. 确定人乳腺癌细胞稳定过表达突变的能力 显性失活 IGFIR 导致骨转移 4. 使用抑制 NF-kappaB 激活的 Ikappa-B 突变体形式研究 NF-kappaB 在骨转移中的作用 5. 检查 IGFIR 和 NF-kappaB 的反义寡脱氧核苷酸 (ODN) 对骨转移的影响