ETIOLOGY AND PROGRESSION OF BREAST CANCER

乳腺癌是一种多方面的疾病，受许多因素影响，包括遗传学以及影响全球大量妇女的内源性和外源性环境因素。我们感兴趣的是确定影响这种疾病过程的环境因素，以及这些环境因素如何与乳腺癌易感基因的产物相互作用。我们正在专门研究乳腺和卵巢易感基因BRCA 1的功能。我们已经发现，使用反义cDNA降低BRCA 1的表达导致致瘤性和锚定独立性的增加，以及在正常生长限制条件下的生长优势，例如卵巢癌细胞中的低雌激素。此外，BRCA 1的缺失可能导致对过氧化氢诱导的凋亡刺激的抵抗。我们已经成功地在细胞中表达外源BRCA 1使用基因组TAR表达载体。该系统的优点是不会发生BRCA 1过表达时观察到的典型毒性。此外，BRCA 1表达的调节类似于内源性基因，如通过维持血清诱导表达所证明的。最后，IGFI和乳腺癌进展的作用正在研究中。我们已经表明，通过用可溶性IGFlR处理细胞降低IGF途径的活化导致乳腺细胞系MDAMB 435的侵袭潜力和转移的显著降低。这将是该项目的最后一年，该项目的组成部分将在2000财年在基因调控组的一个新项目和当前项目# ES-23003中继续。- BRCA 1，BRCA 2，转移，IGFI，凋亡，雌激素

Breast cancer is a multi-faceted disease that is influenced by many factors including genetics, as well as endo- genous and exogenous environmental factors that affects a significant number of women worldwide. 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. We have succeeded in expressing exogenous BRCA1 in cells using a genomic TAR 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 is modulated similar to the endogenous gene as was demonstrated by maintenance of serum inducibility of expression. Finally, the role of the IGFI and the progression of breast carcinoma is being investigated. We 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. This will be the final year for this project, the components of this project will be continued in a new project in the Gene Regulation Group AND in current project # ES-23003 in FY 00. - BRCA1, BRCA2, metastasis, IGFI, apoptosis, estrogen