Project:
Identifying Molecular Targets for Elimination of Premalignant Breast Lesions

Principal Investigator - Thea Tlsty, PhD

ABSTRACT

Metastases, rather than primary tumors, are responsible for >90% of breast cancer-related mortalities. It is believed that metastasis occurs early, probably before the primary tumor is detected. One approach to effectively reduce cancer deaths is to identify premalignant lesions that have a high risk of generating metastases and eliminate them from the breast. We have identified a subpopulation of human breast epithelial cells obtained from disease-free women that have several of the properties seen in breast tumor cells. We hypothesize that these cells, variant human mammary epithelial cells (vHMEC) are precursors to aggressive forms of human breast cancer. In support of this, gene expression profiling of vHMEC using Affymetrix analysis has demonstrated a profile that has many similarities with basal-like tumors. Preliminary data from phage antibody studies have identified novel cell surface markers that are shared by basal-like tumors and vHMEC (potential precursors to malignancy). We hypothesize that novel cell surface markers that are expressed on vHMEC may be retained as these putative precursors progress to pre-malignancy (DCIS) and ultimately a malignant (basal-like) tumor. Cell surface markers shared by rare cells in non-diseased tissue and malignant cells may provide identifying marks for those foci of cells that will progress to malignancy and be used for early detection, risk stratification or targeted intervention. To begin to test this hypothesis we will use technologies developed in SPORE Project 3 (Park/Marks), to (Aim 1) identify vHMEC cell surface markers that may allow us to target cancer precursor cells for therapy before they become invasive tumors. And (Aim 2) evaluate vHMEC biomarkers as potential therapeutic targets. When tested in experiments beyond the scope of this application, these antibodies may potentially serve as new biomarkers for premalignant lesions with a propensity to progress to malignancy and provide molecular targets to eliminate these cells.