email trotman@cshl.edu, phone (516) 367-5054

Our research aims to define the causal events of tumor initiation in order to arrest cancers. To establish causality, we genetically model tumors in mice and validate our findings by comparative analysis with human cancers. In so doing, we have gained surprising insights into how tumorigenesis is prevented in tissues.

Generally, tumor suppressor genes were thought to allow cancer only when completely lost. We discovered that instead, loss of a single copy of the major tumor suppressor PTEN already results in tumor formation, while paradoxically, its complete loss triggers cells to senesce, resulting in a potent growth arrest that blocks development of cancer.

Thus, through stepwise modeling of tumor initiation in mice, we have learned that tumors need to progress in PTEN heterozygosity, a finding that for example is confirmed in the majority of human prostate cancers.

Our current research is testing these results in cancers of the breast and colon where we confirm that subtle variations in PTEN levels dictate benign or aggressive tumor fate. These findings govern two major areas of our research: (1) through understanding its regulation we aim to modulate the remaining PTEN gene or protein in tumors to keep them benign; (2) through introducing specific genetic alterations into Pten heterozygous mice we seek to further define a limited set of key factors that are critical for cancer suppression in this pathway. Based on the outcomes of our research we will select and design therapeutic interventions and test their efficacy in our genetic models.

Trotman, L.C., Wang, X., Alimonti, A., Chen, Z., Teruya-Feldstein, J., Yang, H., Pavletich, N.P., Carver, B.S., Cordon-Cardo, C., Erdjument-Bromage, H., Tempst, P., Chi, S.G., Kim, H.J., Misteli, T., Jiang, X., Pandolfi, P.P. 2007. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell 128: 141-156.

Wang, X., Trotman, L.C., Koppie, T., Alimonti, A., Chen, Z., Gao, Z., Wang, J., Erdjument-Bromage, H., Tempst, P., Cordon-Cardo, C., Pandolfi, P.P., Jiang, X. 2007. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128: 129-139.

Trotman, L.C., Alimonti, A., Scaglion,i P.P., Koutcher, J.A., Cordon-Cardo, C., Pandolfi, P.P. 2006. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523-527.

Chen, Z., Trotman, L.C., Shaffer, D., Lin, H.K., Dotan, Z.A., Niki, M., Koutcher, J.A., Scher, H.I., Ludwig, T., Gerald, W., Cordon-Cardo, C., Pandolfi, P.P. 2005. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436: 725-730.

Trotman, L.C., Niki, M., Dotan, Z.A., Koutcher, J.A., Di Cristofano, A., Xiao, A., Khoo, A.S., Roy-Burman, P., Greenberg, N.M., Van Dyke, T., Cordon-Cardo, C., Pandolfi, P.P. 2003. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1: 385-396.