ETIOLOGY AND PROGRESSION OF BREAST CANCER

乳腺癌是一种多方面的疾病，受许多因素的影响，包括遗传因素，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进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BRCA1的功能。我们发现，使用反义cDNA降低BRCA1的表达会导致致瘤性和锚定独立性的增加，以及在正常生长限制性条件下的生长优势，如卵巢癌细胞的低雌激素。此外，BRCA1的缺失可能导致对过氧化氢诱导的凋亡刺激产生抗性。我们已经成功地使用基因组TAR表达载体在细胞中表达外源性BRCA1。该系统的优点是不会发生BRCA1过表达时观察到的典型毒性。此外，BRCA1的表达与内源性基因的表达调节相似，这可以通过维持血清诱导表达的能力来证明。最后，IGFI在乳腺癌进展中的作用正在研究中。我们已经证明，用可溶性IGFIR处理细胞，降低了IGF通路的激活，导致乳腺细胞系MDAMB435的侵袭潜力和转移显著降低。今年将是本项目的最后一年，本项目的组成部分将在基因调控组的新项目和当前项目# ES-23003中继续进行。- BRCA1, BRCA2，转移，IGFI，细胞凋亡，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