Women's Cancer Section Staff

The Women’s Cancers Section, LP, conducts basic and translational research in breast cancer, primarily using human tissues and model systems. Our long term goal is to advance the prevention and treatment of this disease. Three major projects are under investigation:

Project 1: Basic and translational investigation of the metastasis suppressor gene, nm23. Metastasis is one of the most deadly aspects of breast cancer. Nm23 was the first metastasis suppressor gene identified. Our work focuses on two questions: (1) What is the biochemical mechanism of action of Nm23 in metastasis suppression? We identified the Kinase suppressor of ras (Ksr) protein as a substrate for the histidine protein kinase function of Nm23-H1. Ksr is a scaffold protein for the Erk Map kinase pathway. Future experiments will determine the effect of Nm23-H1 phosphorylation of Ksr on scaffold function, Map kinase activation, and metastasis. (2) Can Nm23-H1 expression be elevated in metastatic breast cells, and will elevated Nm23-H1 expression lead to decreased metastatic disease? Experiments using human cell lines identified both loss of DNA methylation and mammary specific transcription factors/medroxyprogesterone acetate (MPA) as contributors to the elevation of Nm23-H1 expression. Future experiments will examine the effect of MPA on breast carcinoma xenograft Nm23-H1 expression and metastatic potential. Additionally, as part of the NCI Mouse Mammary Models of Cancer, we are generating a Nm23-H1 transgenic mouse; the effect of Nm23-H1 overexpression on mammary development and tumor metastasis will be determined.

Project 2: Molecular characterization of early human breast cancer lesions. We have attempted to identify a molecular map of the progression of normal human ductal epithelia to the first stage of breast cancer, ductal carcinoma in situ (DCIS). We now report the first proteomic analysis of matched human normal ductal/lobular cells and DCIS. This analysis has identified previously unappreciated proteins involved in the intracellular trafficking of membranes, vesicles, and cancer prevention agents. Other proteomic identifications are related to cytoskeletal architecture, chaperone function, tumor microenvironment, apoptosis, and genomic instability. Future investigations will address the phenotypic consequences of selected proteomic identifications, their applicability to cancer prevention and cancer vaccines.

Project 3: Molecular characterization of breast cancer metastases to the brain. This new project examines one of the most deadly aspects of breast cancer metastasis. In collaboration with Dr. Andreas Stark, University of Kiel, Germany, we will be analyze a cohort of human brain metastases of breast cancer by cDNA microarray technology.