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%死于乳腺癌的患者都有骨转移。这些纵隔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增加和最终死亡的主要原因之一。然而，乳腺癌侵袭骨骼的机制仍然知之甚少。骨存储了多种生长因子，由于骨吸收，这些生长因子被释放到骨微环境中。胰岛素样生长因子(IGF)是骨骼中含量最丰富的生长因子。多项临床研究表明，与正常乳腺组织相比，I型胰岛素样生长因子受体(IGFIR)在恶性乳腺肿瘤组织中的表达增加，许多工作人员也发现IGFS能刺激培养的人乳腺癌细胞的增殖。因此，我们提出了一种假说，即骨源性IGFS至少在很大程度上刺激了人乳腺癌细胞在骨微环境中的增殖。另一个目标是研究IGFIR下游信号通路，这些信号通路可能在乳腺癌的骨转移中发挥作用。我们将重点关注转录因子NF-kappaB，因为已经证明IGF-I激活了NF-kappaB，并且已经发现NF-kappaB的结构性激活与人乳腺癌细胞的转移生长过程有关。我们的具体目标是：1.利用抗IGFIR的中和抗体，确定在骨吸收增加时从骨释放的IGF是否加速了人乳腺癌细胞的局部骨转移和在骨中的增殖；2.检测野生型IGFIR稳定过表达对人乳腺癌细胞骨转移能力的影响；3.确定稳定高表达突变的显性负性IGFIR的人乳腺癌细胞发生骨转移的能力；4.利用抑制nf-kappaB活性的突变型ikappa-b研究nf-kappaB在骨转移中的作用5.检测针对igfIR和nf-kappaB的反义寡核苷酸(Odn)对骨转移的影响。