Genes That Modulate Dioxin-Induced Breast Cancer

Institution: Stanford University
Investigator(s): Quan Lu, Ph.D. -
Award Cycle: 2001 (Cycle VII) Grant #: 7FB-0123 Award: $84,731
Award Type: Postdoctoral Fellowship
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2001)
Breast cancer is considered to be both a genetic and environmental disease. While familiar breast cancer accounts for 10-15% of all breast cancer cases, the majority of breast cancer is thought to relate to lifestyle and exposure to environmental pollutants. Dioxins are widespread environmental toxins and are accumulating in foods such as breast milk. Dioxins have been listed by the Environmental Protection Agency (EPA) as a known human carcinogen. Several studies suggest that dioxins may be responsible for some breast cancer cases. It is of great importance to understand how dioxins in human may lead to the development of breast cancer.

We propose that a set of genetic factors are involved in the breast cancer development initiated by dioxins. Changes in these genetic factors may affect the susceptibility of a person to breast cancer development.

I will use an innovative approach dubbed as RHKO to search for the genetic factors. This method was invented in my mentor Dr. Stanley Cohen's lab in 1996 (Dr. Cohen is also the inventor of the DNA recombination technology that is widely used for drug discovery). Since its invention, RHKO has been successfully used to discover at least four tumor suppressors (genetic factors that inhibit tumor growth). Another major method I am going to use is called 'human cDNA microarray', a method developed by our Stanford colleagues Dr. Pat Brown and David Brown. This array technology can be used to study thousands of genes simultaneously and thus offer a very fast and efficient tool for gene discovery.

The proposal addresses an important but poorly understood process (how dioxins may increase the risk of human breast cancer). The approaches that will be used are novel and never before been applied to study dioxin-induced carcinogenesis. I believe the proposed study will have several aspects of significance. First, identification of these genetic factors will help us to understand the ways by which dioxins influence breast cancer risk. Second, the study may provide valuable information to discover new targets for drug development, which is needed for prevention, diagnostics, and treatment of cancers caused by dioxin exposure. Finally the study may also benefit other human cancers since dioxins cause cancers in other human cells.

Final Report (2003)
Dioxins, widespread and persistent environmental pollutants, are a known human carcinogen and may contribute to the development of breast cancer. It is of great importance to understand the genetic mechanism by which dioxin exposure leads to carcinogenesis. The goal of this proposal is to utilize novel genetic screening tools including RHKO (random homozygous knock out), to identify genes whose inactivation increases susceptibility of human breast cells to dioxin-initiated tumorigenesis. To this end I have created RHKO libraries in an immortalized human cell line. I also developed an antisense human EST (expressed sequence tag) library as an alternative RHKO genetics screening tool. Using a high through-put genomic tool known as cDNA microarray to compare gene expression profiles between dioxin-treated and non-treated control cells, I identified, in addition to known dioxin-induced genes, several genes previously not known to be involved in dioxin-induced tumorigenesis.

Identification of dioxin-susceptible tumor genes and their associated pathways will help elucidate the molecular mechanism of dioxin-induced carcinogenesis in breast and other human tissues. Furthermore, such study may provide valuable information needed for prevention, diagnostics, and treatment of cancers induced by dioxin exposure. For example, a screen for polymorphism of dioxin-susceptible tumor genes may identify dioxin-sensitive populations, which will aid the prevention of dioxin-induced cancers.

TSG101 interaction with HRS mediates endosomal trafficking and receptor down-regulation
Periodical:Proceedings of the National Academy of Sciences of the United States of America
Index Medicus: Proc Nat Acad Sci, U S A
Authors: Lu Q, Hope LW, Brasch M, Reinhard C, Cohen SN
Yr: 2003 Vol: 100 Nbr: 13 Abs: Pg:7626-31