CHEMOPREVENTION OF BREAST AND OVARIAN CANCER

拟议研究的长期目标是确定乳腺和卵巢组织中的特定生物标志物，这些生物标志物来自受有效化学预防剂调节的高风险个体，因此可以作为未来化学预防试验的替代终点。这些研究将涉及几个机构的临床研究人员的合作，包括德克萨斯大学圣安东尼奥健康科学中心，MD安德森癌症中心，贝勒医学院和德克萨斯大学西南医学中心。这些机构以前组成了得克萨斯州癌症遗传学联盟，并有活跃的高风险癌症遗传学诊所。具体项目包括：（1）使用RXR选择性维甲酸调节乳腺生物标志物。该项目是一项临床试验，其中新型RXR选择性维甲酸LGD 1069（Targretin）将用于调节乳腺癌高危女性乳腺活检中的潜在生物标志物。(2)卵巢癌的化学预防：使用芬维A胺和口服避孕药的标记物调节。该项目将研究口服避孕药，合成类维生素A 4 HPR或其组合是否会调节与肿瘤和凋亡相关的光纤检测卵巢表面光谱特性，并改变乳腺和卵巢细胞的表达。在这个项目中，我们将使用cDNA表达阵列来表征LGD 1069在正常和恶性人类乳腺细胞中上调或下调的特定基因。我们将定义这些类维生素A调节基因表达变化的生物学效应，并确定某些变化是否是动物模型现有组织中成功化学预防的标志物。这些LGD 1069调节基因在本项目中确定，然后将被纳入项目1，以确定它们是否也在类维生素A处理的人类乳腺组织中调节。拟议的研究将得到三个核心设施的支持：病理学/免疫组织化学核心，生物统计学核心和行政核心。这些高度互动的项目将确定这些新的化学预防策略是否调节特定的生物标志物，因此是预防乳腺癌和卵巢癌的有前途的药物，并表明这些标志物中的哪一个可能是最有用的终点，在以后的大规模销售预防试验中，在家族性乳腺癌和卵巢癌的高风险妇女。因此，这些研究最终应有助于降低这些常见癌症的发病率和死亡率。

The long-term goal of the proposed studies is to identify specific biomarkers in breast and ovarian tissue from high-risk individuals who are modulated by effective chemopreventive agents, and may therefore serve as surrogate endpoints in future chemoprevention trials. The studies will involve the collaboration of clinical investigators at several institutions, including the University of Texas Health Science Center at San Antonio, MD Anderson Cancer Center, Baylor Medical College, and the University of Texas Southwestern Medical Center. These institutions have previously formed the Texas Cancer Genetics Consortium, and have active high-risk cancer genetics clinics. Specific projects include: (1) Modulation of Breast Biomarkers using an RXR-Selective Retinoid. This project is a clinical trial in which the novel RXR-selective retinoid LGD1069 (Targretin) will be used to modulate potential biomarkers in breast biopsies from women with high risk of breast cancer. (2) Chemoprevention of Ovarian Cancer: Marker Modulation using Fenretinide and Oral Contraceptives. This project will investigate whether oral contraceptives, the synthetic retinoid 4HPR or their combination, will modulate fiber-optically detected ovarian surface spectral properties associated with neoplasia and with apoptosis, and will change the expression of Breast and Ovarian Cells. In this project, we will characterize specific genes which are up or down-regulated in normal and malignant human breast cells by LGD1069, using cDNA expression arrays. We will define the biological effects of changes in expression of these retinoid-regulated genes and determine whether certain changes are markers of successful chemoprevention in existing tissues from an animal model. These LGD1069-regulated genes identified in this project will then be included in Project 1 to determine whether they are also modulated in retinoid-treated human breast tissue. The proposed studies will be supported by three core facilities: a pathology/immuno- histochemistry core, a biostatistics core, and an administrative core. These highly interactive projects will determine whether these novel chemopreventive strategies modulate specific biomarkers and are therefore promising agents for the prevention of breast and ovarian cancer, as well as indicating which of these markers might be most useful as endpoints in later, large-sale prevention trials in women at high risk of familial breast and ovarian cancer. Thus, these studies should ultimately serve to reduce the incidence and mortality of these common cancers.