The main objective in our laboratory is to understand the molecular defects (both genetic and epigenetic) that contribute to the initiation and maintenance of malignancy in human breast cancer cells. Such human solid tumors show a steep age-dependent increase in incidence. This sharp increase is thought to be due to accumulated changes in gene expression and function that over time favor the development of growth autonomy and invasiveness in susceptible cells.
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.
Beliveau, A. and Yaswen, P. Soothing the watchman: telomerase reduces the p53-dependent cellular stress response. Cell Cycle: 6:1284-7, 2007.
Quinlan, K., Verger, A., Yaswen, P., and Crossley, M. Amplification of zinc finger gene 217 (ZNF217) and cancer: when good fingers go bad. Biochim Biophys Acta. 1775:333-40, 2007.
Beliveau, A., Bassett, E., Lo, A.T., Garbe, J., Rubio, M.A., Bissell, M.J., Campisi, J., and Yaswen, P. p53-dependent integration of telomere and growth factor deprivation signals. Proc. Nat. Acad. Sci. (USA), 104:4431-6, 2007.
Krig, S.R., Jin, V.X., Bieda, M.C., O'geen, H., Yaswen, P., Green, R., and Farnham, P.J. Identification of genes directly regulated by the oncogene ZNF217 using ChIP-chip assays. J. Biol. Chem. 282:9703-12, 2007.
Yaswen, P. and Campisi, J. Oncogene-induced senescence pathways weave an intricate tapestry. Cell 128:233-4, 2007.
Quinlan, K.G.R., Nardini, M., Verger, A., Francescato, P., Yaswen, P., Corda, D., Bolognesi, M., and Crossley, M. Specific recognition of ZNF217 and other zinc-finger proteins at a surface groove of CtBPs. Mol. Cell Biol.: 26:8159-72, 2006.
Fournier, M., Martin, K.J., Xhaja, K., Bosch, I., Yaswen, P., and Bissell, M.J., Gene expression signature in organized and growth arrested mammary acini predicts good outcome in breast cancer. Cancer Res. 66:7095-102, 2006.
Huang, G., Krig, S., Kowbel, D., Xu, H., Hyun, B., Volik, S., Feuerstein, B., Mills, G.B., Stokoe, D., Yaswen, P., and Collins, C. ZNF217 suppresses cell death associated with chemotherapy and telomere dysfunction. Hum Mol Genet. 14:3219-25, 2005.
Nijjar, T., Bassett, E., Garbe, J., Takenaka,Y., Stampfer, M.R., Gilley, D., Yaswen, P. Accumulation and altered localization of telomere-associated protein TRF2 in immortally transformed and tumor-derived human breast cells. Oncogene 24:3369-3376, 2005.
Rodier, F., Kim, S-H., Nijjar, T., Yaswen, P., and Campisi, J. Cancer and aging: The importance of telomeres in genome maintenance. Int. J. Biochem. Cell Biol.: 37: 977-990, 2005.