in Environmental Exposures and Health
The "B" (Breast Cancer) Team
Exposure to ubiquitous environmental chemicals, such as polycyclic aromatic hydrocarbons (PAH), may contribute to human cancers, including cancers of breast tissue. In animals, PAH induce tumors in part by activating the aryl hydrocarbon receptor (AhR)/transcription factor. Historically, investigations into AhR-regulated carcinogenesis have focused on AhR-dependent transcriptional regulation of cytochrome P450 (CYP) enzymes which oxidize PAH to mutagenic intermediates. However, recent studies suggest that the AhR directly regulates cell growth. Recently, the Sherr laboratory has demonstrated that greater than 90% of all human cancers evaluated expressed extremely high levels of AhR that appeared to be constitutively active despite the absence of environmental AhR agonists such as PAH. Down-regulation of AhR activity with pharmacologic agents or through molecular techniques alters cancer cell growth, suggesting rational strategies for AhR-targeted treatment or prevention of breast cancers.
Five members of the “B” team are investigating the molecular mechanisms through which the AhR may regulate breast cancer growth. Xinhai Yang, Ph.D. is evaluating the interaction of the AhR with several genes that contribute to breast cancer growth and survival. They have shown that the AhR represses expression of the c-myc oncogene and may similarly regulate genes involved in regulating tumor cell apoptosis. Dr. Yang is in the process of genetically engineering a transgenic mouse line in which the AhR is over-expressed in mammary epithelial cells. These studies will increase our understanding of the factors which maintain constitutive AhR activity and dysregulated cell growth in neoplasms.
Donghui Liu, M.S., leads a project designed to evaluate how the AhR affects mammary cell growth in the absence of environmental chemicals. She has demonstrated that down-regulation of the AhR through transduction of an AhR repressor plasmid transported on a lentiviral vector profoundly slows mammary tumor growth. These findings suggest the possibility of targeting the AhR for cancer therapy.
Sandra Solomon, a predoctoral student in the Pathology Department and the Immunology Training Program, has been studying AhR expression and function in human mammary tumors and in murine tumors induced with an environmental chemical. She has noted a profound up-regulation of the AhR which appears to correlate with aberrant expression of several other genes implicated in mammary gland tumor development. These studies should help explain how the AhR influences and is influenced by known contributors to tumor development. Ms. Solomon also is evaluating the effects of naturally-occurring dietary flavonoids on mammary tumor growth.
All of the work performed by the “B” team is performed in collaboration with Drs. Gail Sonenshein (Biochemistry) and David Seldin (Medicine) under the aegis of a program project grant on breast cancer. This program project is supported by the National Institute of Environmental Health Sciences.