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.
