The disease phenylketonuria (PKU) is caused by mutations in the gene coding for phenylalanine hydroxylase (PAH) which results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites. Among these metabolites is phenylacetic acid, or the ionized form of the molecule phenylacetate (PA). Recently, PA has come under intense investigation due to its demonstrated anticancer activity against a variety of malignancies, including breast and prostate cancers. These findings suggest the possibility that PKU may offer protection against cancer through chronically elevated blood levels of PA. The investigator's overall objective is to test this hypothesis. This will be accomplished by studies involving two in vivo mouse models.
Specific Aim 1 will assess the ability of therapeutic intervention with a PA analogue to inhibit estrogen-dependent carcinogenesis using the investigator's existing aromatase transgenic mouse colony. In these experiments, the PA derivative 4-chloro-PA will be chronically administered to the mice in their drinking water and its chemopreventative activity on the development of preneoplastic / neoplastic lesions assessed.
Specific Aim 2 will test the hypothesis that PKU can protect against breast cancer using """"""""PKU mice"""""""". These studies will utilize an established PKU mouse model (ENU2/2), which has a mutation in the gene coding for PAH and display a range of phenotypic characteristics comparable to those of affected human individuals. The ENU2/2 mice will be treated with the chemical carcinogen DMBA under different protocols and the resulting induction of mammary tumors compared with control mice of the same genetic background. Taken together, the information gained from these in vivo studies will determine whether the genetic disorder that results in PKU can protect against breast cancer whose etiology may involve hormonal and/or environmental factors (carcinogens).
| Sidell, Neil; Hao, Lijuan; Pasquali, Marzia et al. (2009) Carcinogenic effects in a phenylketonuria mouse model. PLoS One 4:e4292 |
| Sidell, Neil; Kirma, Nameer; Morgan, Eddie T et al. (2007) Inhibition of estrogen-induced mammary tumor formation in MMTV-aromatase transgenic mice by 4-chlorophenylacetate. Cancer Lett 251:302-10 |
| Sidell, N; Pasquali, M; Malkapuram, S et al. (2003) In vitro and in vivo effects of easily administered, low-toxic retinoid and phenylacetate compounds on human neuroblastoma cells. Br J Cancer 89:412-9 |
