Our current studies indicate that limits on the proliferative potential of cultured normal human mammary epithelial cells (HMEC) may be consequences of pathways that exist to suppress tumorigenicity. HMEC employ several mechanisms to prevent unlimited growth. Repression of telomerase, a specific enzyme that maintains telomeres, is one mechanism that may provide a stringent limit to the number of replications a single cell lineage can undergo, thus limiting the opportunity for deleterious mutations to accumulate within that lineage. However, with advancing age, rare mutations that do arise despite the limit on replicative life span could be complemented by chromosomal aberrations arising in cells with critically short telomeres. By studying the chromosomal aberrations and epigenetic changes that lead to maintenance or reactivation of telomerase, we expect to learn more about a potentially rate-limiting step in epithelial tumor progression.

Specific ongoing projects in our laboratory include: a) examining the regulation of the hTERT gene, encoding the catalytic subunit of telomerase, in closely related non-malignant or malignant breast cell cultures; b) determining whether aberrant self-renewal and tumorigenicity of breast cancer stem cells can be overcome by stimulation of differentiation pathways downstream of oncogenic defects; c) determining how exposure to radiation and environmental agents contributes to HMEC transformation; d) establishing a possible mechanism by which ZNF217, an oncogene amplified and overexpressed in many breast cancers, may contribute to cancer progression; e) determining how soluble and insoluble microenvironmental factors affect growth control in HMEC.