ETIOLOGY AND PROGRESSION OF BREAST CANCER

美国每八个女人中就有一个 在她的一生中会受到乳腺癌的影响。乳腺癌是一 受多种因素影响的多方面疾病，包括 遗传学，以及内源和外源环境 因素我们感兴趣的是确定环境因素 影响这种疾病的进程， 环境因素与乳腺癌产物的相互作用 易感基因我们专门研究 乳腺和卵巢易感基因BRCA1。我们发现 使用反义cDNA降低BRCA1的表达， 致瘤性和锚定独立性增加， 以及在正常生长限制条件下的生长优势， 如卵巢癌细胞中雌激素水平低。此外，损失 BRCA 1可能导致对由细胞凋亡诱导的细胞凋亡刺激的抵抗。 过氧化氢表达的额外研究 BRCA1蛋白在乳腺癌组织中的表达呈交替性变化， BRCA1蛋白的剪接形式。我们目前正试图 开发BRCA1的诱导表达系统， BRCA1介导的信号转导有待阐明。我们有 成功地在细胞中表达外源性BRCA1， 基因组表达载体。该系统的优点是， BRCA1过表达的典型毒性 不发生此外，BRCA 1表达可能受到调节， 类似于内源基因。最后，政府间森林问题论坛和 正在研究乳腺癌的进展。我们有 表明通过饮食限制降低IGFI的表达， 减少小鼠中晚期膀胱癌的形成。我们 现在我将这一观察结果扩展到了乳腺肿瘤的发展 并且已经表明，通过降低IGF途径的活化， 用可溶性IGFlR处理细胞， 降低乳腺细胞系的侵袭潜力和转移， MDAMB435.

One out of every eight women in the United States will be affected by breast cancer in her lifetime. Breast cancer is a multi-faceted disease that is influenced by many factors including genetics, as well as endo- genous and exogenous environmental factors. We are interested in determining the environmental agents that influence the course of this disease and how these environmental factors interplay with products of breast cancer susceptibility genes. We are specifically investigating the function of the breast and ovarian susceptibility gene, BRCA1. We have found that decreased expression of BRCA1 using antisense cDNA results in an increase in tumorigenicity and anchorage-independence, as well as a growth advantage in normal growth restrictive conditions, such as low estrogen in ovarian cancer cells. In addition, loss of BRCA1 may result in resistance to apoptotic stimuli induced by hydrogen peroxide. Additional investigation of the expression of BRCA1 protein revealed the distinct expression of an alternately spliced form of the BRCA1 protein. We are currently trying to develop an inducible expression system for BRCA1 that will allow BRCA1-mediated signal transduction to be elucidated. We have succeeded in expressing exogenous BRCA1 in cells using a genomic expression vector. The advantage of this system is that the typical toxicity that is observed with BRCA1 overexpression does not occur. In addition, BRCA1 expression may be modulated similar to the endogenous gene. Finally, the role of the IGFI and the progression of breast carcinoma is being investigated. We have shown that decreased expression of IGFI by dietary restriction can reduce the formation of advanced bladder carcinomas in mice. We have now extended this observation to breast tumor development and have shown that decreased activation of the IGF pathway by treatment of cells with the soluble IGFIR results in a significant decrease of invasion potential and metastases of the breast cell line, MDAMB435.