Etiology and Prevention: Finding the Underlying Causes

Overview: Despite the identification of breast cancer genes and other risk factors, the disease strikes most women at random. There are causes of the disease that cannot be explained by the analysis of tumors in the laboratory setting. What are environmental and biological factors that interact to increase a woman.s risk of developing breast cancer? How do these factors impact different communities of women in California? Knowing what causes breast cancer will allow us to take steps to prevent it.

Funding Data:
 

Proportion of Total

Etiology and Prevention grants awarded in 2004

8

19%

Funded amount:

$3,901,663

27%

Etiology and Prevention Portfolio Summary:

Two of CBCRP's research topics are represented in this section:

Although there has been renewed interest very recently in explanations for the causes of breast cancer based on non-estrogen factors (e.g., viruses, particularly the mouse mammary tumor virus), the view of breast cancer as largely an uncontrolled, estrogen-fueled cell growth process received most of the attention in our Etiology and Prevention topic this year. Three newly funded grants look at suppressing the aromatase (an enzyme critical in the biosynthesis of estrogen) pathway, which in turns limits estrogen production. This research interest has received new impetus from the results the ATAC (Arimidex, Tamoxifen, Alone or in Combination) clinical trial that has shown aromatase inhibitors to be superior to antiestrogen compounds in treating breast cancers. Ikuko Kijima a doctoral student at the Beckman Research Institute of the City of Hope will focus on the aromatase gene and examine its gene regulatory factors. The PI believes that novel regulatory sites may play an important role in acting as enhancers or repressors of aromatase production. This research may aid in refinement of novel therapeutic approaches to reduce aromatase gene activity. Shiuan Chen and Melanie Ruth Palomares also at the Beckman Research Institute of the City of Hope will determine if grape seed extracts (GSE) given to human volunteers will reduce the level of circulating estrogens in normal postmenopausal women at increased risk for breast cancer, and they will look at the safety and tolerability of these extracts. Shiuan Chen is funded through a separate grant to study whether a white button mushroom extract is a potent aromatase inhibitor. If this is true, then a readily available and affordable strategy to reduce breast cancer risk would be available to the public.

Two newly funded grants examine the role of estrogen and estrogen receptors. Dale Leitman at the University of California, San Francisco, will examine the possibility of chemoprevention using substances from Chinese herbal remedies that may interact with a type of estrogen receptor, called ERβ. There is some preliminary data showing that activation of this receptor may be protective against breast cancer. Dr. Leitman will screen for compounds that have ERβ activity and test them in a mouse model for effectiveness. This is a necessary step before possible human trials. While most of the research on the effects of estrogen exposure and breast cancer has adult women as its subject, Peggy Reynolds with the California Department of Health Services will look at whether prenatal exposure to maternal estrogens may play a role in later breast cancer development. This case-control study will test the hypothesis that selected prenatal and perinatal factors are related to subsequent breast cancer risk in young Californiaborn women. Factors such as infant birth weight, gestational age at birth, and maternal characteristics will be looked at in consideration with the possible modifying effects of socioeconomic factors (SES) and region of birth on the relationship between birth characteristics and breast cancer risk.

Two newly-funded grants focus on dietary factors that may modulate breast cancer risk and serve in chemoprevention. Anna Wu and her team at the University of Southern California is examining soy and green tea intake and breast cancer among Chinese, Japanese, and Filipino women. Dr. Wu has found decreasing breast cancer risk with increasing levels of green tea intake, particularly among women without high soy intake. Confirmation of these findings is important, as are more details on dose response and the timing necessary to reduce risk (i.e., whether soy intake in adulthood vs. childhood). She will also look at variations in certain genes for associated metabolic interactions which may affect risk, and she will determine the relationship between blood estrogen levels and dietary intake of soy and tea. Mai Brooks and Jian Rao, from the University of California, Los Angeles, will look to see if polyphenon compounds in green tea have direct action in the breast to decrease both cell growth and expression of suspected tumor growth factors when taken orally. They propose the use of ductal lavage technology to measure changes in certain angiogenic compounds (those associated with the process of blood vessel formation that supports tumor growth) that are found in nipple fluid. These compounds may also be associated with pre-cancerous breast atypia. If successful, they will then know more about the effect of green tea on breast physiology and whether certain compounds in breast fluid can serve as markers for evaluating the effects of green tea.

Urged on by community concerns, Myrto Peatras at the California Department of Health Services, Public Health Institute is funded to see if there is a possible link between polybrominated diphenyl ethers (PBDEs) and breast cancer. This study will compare the levels of the byproducts of these compounds (commonly used as flame retardants) in women who have breast cancer to those who do not. PDBEs were introduced in the late 1970s and the PI has already shown that these potentially estrogenmodulating toxins are present in the environment and in human sera.

Etiology and Prevention Grants Funded in 2004:

Etiology

Control of Aromatase Expression in Breast Cancer
Ikuko Kijima
Beckman Research Institute of the City of Hope
Award type: Dissertation
Duration: 2 years
$60,000

PDBEs in Tissues of Women with and Without Breast Cancer
Myrto Petreas, Ph.D., M.P.H.
California Department of Health Services
Award type: IDEA
Duration: 1.5 years
$85,901

Birth Characteristics and Breast Cancer in Young Women
Peggy Reynolds, Ph.D.
California Department of Health Services
Award type: RFA
Duration: 3 years
$906,386

Prevention

Surrogate Markers for Green Tea
Mai Brooks, M.D., FACS and Jian Rao, M.D.
University of California, Los Angeles
Award type: TRC Pilot
Duration: 1 year
$100,000

Breast Cancer Prevention with Phytochemicals in Mushrooms
Shiuan Chen, Ph.D.
Beckman Research Institute of the City of Hope
Award type: RFA
Duration: 3 years
$766,376

Grape Seed as Aromatase Inhibitor for Breast Cancer Risk
Shiuan Chen, Ph.D. and Melanie Ruth Palomares, M.D.
Beckman Research Institute of the City of Hope
Award type: TRC Pilot
Duration: 1 year
$171,996

Breast Cancer Chemoprevention with Dietary Herbal Estrogens
Dale Leitman, M.D., Ph.D.
University of California, San Francisco
Award type: STEP
Duration: 2 years
$200,000

Tea, Genes, and their Interactions on Breast Cancer
Anna H. Wu, Ph.D.
University of Southern California
Award type: RFA
Duration: 3 years
$1,611,004