We have demonstrated that in utero exposure of rats to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) suppresses the development of chemically induced mammary cancer in the adult female offspring. We have shown that mammary gland maturation accounts for the cellular mechanism of mammary cancer susceptibility. However, little is known about the underlying mechanisms at the genome and protein levels. We hypothesize that in utero exposure to TCDD acts via imprinting mechanism to alter the mammary gland proteome that in turn determines cancer susceptibility.
The Specific Aim 1 is to investigate DNA methylation as imprinting mechanism of in utero TCDD exposure predisposing for mammary cancer susceptibility. From mammary glands of prepubertal and adult rats exposed in utero + TCDD, we will investigate DNA methyltransferases (Dnmts) and DNA base methylation of specific genes containing large CpG rich promoter regions. Hypermethylation is associated with gene silencing. We will focus our attention on estrogen receptor alpha (ER-alpha), glutathione S transferase-pi (GST-pi) and mammary derived growth inhibitor (MDGI). The protein products of these genes have been associated with the early stages of mammary cancer development.
Aim 2 is to identify proteins that are differentially expressed in mammary glands of rats exposed in utero to TCDD Characterization of proteins that are differentially expressed during the period of mammary gland differentiation (day 21) and at time of carcinogen exposure (day 50) in the DMBA-rat model (in the absence of the original chemical modulator, TCDD) will identify proteins that predetermine mammary cancer susceptibility. We will identify differentially expressed proteins from mammary glands using 2-D gel electrophoresis and MALDI-TOF spectrometry Identification of methylated gene promoters and individual proteins/protein clusters that are differentially expressed will aid in understanding how in utero exposure to environmental chemicals can program predisposition for cancer.
| Jenkins, Sarah; Betancourt, Angela M; Wang, Jun et al. (2012) Endocrine-active chemicals in mammary cancer causation and prevention. J Steroid Biochem Mol Biol 129:191-200 |
| Jenkins, Sarah; Rowell, Craig; Wang, Jun et al. (2007) Prenatal TCDD exposure predisposes for mammary cancer in rats. Reprod Toxicol 23:391-6 |
