Inherited genetic risk accounts for no more than 10-15% of all breast cancer cases, hence it has been suggested that the environment plays a significant role in the cause of this cancer. We have hypothesized that early periods of exposure to hormonally-active chemicals are critical for causing developmental changes to the mammary tissue and that these alterations can set the biochemical """"""""blue-print"""""""" that can play an important role in being susceptible for breast cancer as adults. We propose to investigate the potential of prenatal exposure to the bioactive food component, resveratrol, and the environmental contaminant, TCDD, as estrogen agonist and antagonist respectively to alter mammary cancer susceptibility in the adult offspring.
Specific aim 1 will be to investigate the potential of resveratrol and TCDD to alter mammary gland development as evaluated from mammary whole mounts and proliferation cell nuclear antigen staining will be used as an index of cell proliferation in mammary glands of resulting 21 day old fetuses and 50 day old adult offspring.
Aim 2 will identify proteins that are differentially expressed in mammary glands using 2-D gel electrophoresis and MALDI-TOF spectrometry, followed by immuno-techniques for validation. Characterization of proteins that are differentially modulated will identify novel pathways that play a role in determining cancer susceptibility.
Aim 3 will determine the effects of prenatal exposure to resveratrol and TCDD, alone and in combination, for predisposition to chemically-induced mammary cancer using the 7,12 dimethylbenz[a]anthracene-rat model. Also, we will record body and uterine weights, day of vaginal opening and evaluate estrous cyclicity as indicators of endocrine function. Changes in susceptibility to mammary cancer will be correlated with gland development, epithelial and stromal cell proliferation, endocrine status and proteomic signatures. Characterization of novel pathways that are differentially modulated at critical periods will identify key proteins that play a role in determining cancer susceptibility. Programming breast cancer chemoprevention from in utero exposure to a nutritional agent would be a novel breakthrough for women's health. ? ? ?
| 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 |
