Etiology and Prevention: Finding the Underlying Causes

Overview: Although our foundation of knowledge for the basic science aspects of breast cancer has expanded greatly over the past ten years, there still remains a gap in our strategies for large-scale prevention due to uncertainties over the underlying causes of the disease and their relative importance. The Breast Cancer and Environmental Research Act of 2005 (S.737/ H.R. 2231), which amends the existing Public Health Service Act, summarizes many of the key issues related to the etiology and risk for breast cancer as follows:

• “Breast cancer is the second leading cause of cancer deaths among American women.
• More women in the United States are living with breast cancer than any other cancer (excluding skin cancer). Approximately 3,000,000 women in the United States are living with breast cancer, about 2,000,000 of which have been diagnosed and an estimated 1,000,000 who do not yet know that they have the disease.
• Breast cancer is the most commonly diagnosed cancer among women in the United States and worldwide (excluding skin cancer). In 2005, it is estimated that 269,730 new cases of breast cancer will be diagnosed among women in the United States, 211,240 invasive breast cancers and 58,490 cases of ductal carcinoma in situ (DCIS).
• Approximately 40,410 women in the United States will die from the disease in 2005. Breast cancer is the leading cause of cancer death for women in the United States between the ages of 20 and 59, and the leading cause of cancer death for women worldwide.
• A woman who lives into her 80s in the United States has a 1 in 7 chance of developing invasive breast cancer in her lifetime. This risk was 1 in 11 in 1975. In 2005, a new case of breast cancer will be diagnosed every 2 minutes and a woman will die from breast cancer every 13 minutes.
• All women are at risk for breast cancer. About 90 percent of women who develop breast cancer do not have a family history of the disease.“

Although there is an extensive laundry list of factors associated with increased and decreased risk for breast cancer, controversy exists over the relative importance of diet, exercise, family history, pregnancy, alcohol, hormone replacement therapy, and others. Because the vast majority of all breast cancers are sporadic and not associated with hereditary risk factors (e.g. BRCA genes), interest has shifted to looking at “the environment” to explain the elevated levels of breast cancer over the past 20-30 years. Although environment can mean many things, a topic of special focus in California is the exposure to synthetic chemicals and radiation. In addition, the focus on the environment is expected to shed light on disparities in breast cancer incidence, ethnic factors, and variations across diverse communities. Thus, researchers are looking both inside cancer cells for clues to the key genes that initiate and cause cancer to progress and outside of the individual to find external causative factors that might be eliminated or modified to reduce risk.

Etiology and prevention (or risk reduction) go hand-in-hand. The Breast Cancer Prevention Trial (BCPT) to study tamoxifen in high-risk women and the STAR (Study of Tamoxifen and Raloxifene) trial have yielded promising, often controversial results, but “reduction” falls far short of prevention for most women. More complete results of the STAR trial are expected in 2006.

Although prevention research has focused on the role of estrogen and modification of lifestyle factors (diet, exercise), more work is needed on such topics as androgens, the ER-? form of the estrogen receptor, and more complex tissue interactions in the breast (stromal-epithelial) that might be influenced by aging and environmental factors.

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

• Etiology: The Role of the Environment and Lifestyle
• Prevention and Risk Reduction: Ending the Danger of Breast Cancer

Funding Data:
 

Proportion of Total

Etiology and Prevention grants awarded in 2005

8

15%

Funded amount:

$1,151,051

15%

Four newly funded grants focus on the etiology of breast cancer. A Joining Forces Conference award to Susan Love, M.D., supported the 4th International Symposium on the Intraductal Approach to Breast Cancer. The meetings were held on March 10-13, 2005, in Santa Barbara and hosted by the Dr. Susan Love MD Research Foundation, Pacific Palisades. More than 100 researchers, clinicians, and patient advocates from California and elsewhere met to discuss the current status and future of this technology. The intraductal method involves obtaining breast duct fluid via the nipple either as aspirate fluid or as a lavage. The cells and fluid can then be analyzed for pre-cancerous and cancerous proteins, genes, and cytology.

Two newly funded grants consider hormonal factors. Yanyan Hong at the Beckman Research Institute of the City of Hope received dissertation funding to characterize the three-dimensional structure of human aromatase. It is the aromatase pathway that largely determines estrogen levels in postmenopausal women, and aromatase inhibitors are especially effective in preventing recurrence in postmenopausal women. Structural information on aromatase may enable the discovery of additional compounds for the chemoprevention and treatment of breast cancer.

Wei Wang, Ph.D., at the University of Southern California received a postdoctoral fellowship to look at the possible role played by the androgen receptor in breast cancer. In women, this “male” hormone may have a dual role, indirectly as a source of estrogen (thus increasing risk), and directly by binding to a breast cell receptor (thus possibly protective). The overall impact on risk may depend on the genetically determined balance between the two actions. Dr. Wang will examine DNA from a large sample of African American, Hispanic, and white women.

Stanley Rockson, M.D., at Stanford University will investigate the development of lymphedema, a condition that involves swelling of the soft tissues of the arm or hand. This condition, a result of surgical disruption of the lymph system of the arm, occurs in as many as 25%-50% of women who undergo complete lymph node removal as part of the breast cancer surgery. While not life-threatening, the swelling may be accompanied by numbness, discomfort, and sometimes infection, and has a profound impact on quality of life. Dr. Rockson will consider the hypothesis that insulin resistance contributes to the risk of lymphedema and that genetic variation in the ”forkhead” transcription factor (FOXC2) gene mediates part of the risk. The FOXC2 gene has been shown to be mutated in individuals with inherited lymphedema syndromes, and its protein product regulates several aspects of adipocyte (fat cell) metabolism.

Four newly funded CBCRP grants are concerned with prevention and risk reduction.

There are two forms of the estrogen receptor, ER-α and ER-ß, and their presence and relative amounts may determine whether estrogen-receptor modulators (such as Tamoxifen) are effective in certain women. Surprisingly, little work has been performed on the ER-ß to test this idea. Peter Kushner, Ph.D., at the University of California, San Francisco, will test the efficacy of a new estrogen receptor modulator, diarylpropionitrile (DNP) as a chemopreventive agent for breast cancer for women of all ages. Dr. Kushner will use cell studies and a special breed of mouse (MMTV-c-neu) to test the ability of DPN to inhibit estrogen-driven breast cancer cell proliferation in culture, and prevent the occurrence of hyperplasia.

Melanie Palomares, M.D., at the Beckman Research Institute of the City of Hope, will study whether grape seed extract (GSE), a powerful inhibitor of aromatase activity in mice, can be taken by human subjects without adverse affects. GSE is undergoing a small Phase I clinical trial and Dr. Palomares’ study is meant to examine whether there are any longer-term side effects. Blood samples will be examined by proteomics techniques to specifically see whether GSE affects testosterone-related hormones, cholesterol and blood clotting proteins, insulin resistance, and blood vessel growth.

Current chemoprevention strategies rely primarily on selective estrogen-receptor modulators (SERMs) using a single drug, and while they do have benefit for some women, it is clear that there is room for much improvement. Jeffrey Gregg, M.D., at the University of California, Davis, will investigate whether combination chemoprevention could be more effective. Using a mouse model bred to mimic the biology, pathology, and behavior of human ductal carcinoma in situ (DCIS), mice will be treated with different dosages and combination of agents, and the effectiveness and toxicity of each treatment will be assessed.

Increased breast mammographic density is one of the strongest predictors of breast cancer risk, but we know little about the biological basis of this effect. Thea Tlsty, Ph.D., from University of California, San Francisco, will investigate whether the supporting breast stromal (fibroblast cell) tissue can interact with early developing breast cancer cells to alter tumor initiation and progression. Dr. Tlsty will implant combinations of fibroblasts from dense vs. normal human breasts along with human breast tumor cells using mice as a host. The goal is to identify clinically relevant biomarkers for the early genetic and epigenetic events in carcinogenesis that reflect altered stromal-epithelial interactions. Understanding the risk factors associated with dense breast stromal tissue might lead to novel preventive strategies.


Etiology and Prevention Grants Funded in 2005:

Etiology

Structural Characterization of Aromatase
Yanyan Hong, M.S.
Beckman Research Institute of the City of Hope
Award type: Dissertation
$70,750

4th International Symposium on the Intraductal Approach to the Breast
Susan Love, M.D.
Susan Love MD Foundation
Award type: Joining Forces Conference
$25,000

Breast Cancer Lymphedema: Role of Insulin Resistance/FOXC2
Stanley G. Rockson, M.D.
Stanford University
Award type: IDEA
$234,178

Androgen Receptor Gene and p21 Gene in Breast Cancer
Wei Wang, M.D.
University of Southern California
Award type: Postdoctoral fellowship
$134,998

Prevention and Risk Reduction

Targeted Chemoprevention in a Mouse Model for DCIS
Jeffrey P. Gregg, M.D.
University of California, Davis
Award type: IDEA
$135,726

Estrogen Receptor Beta Agonists to Prevent Breast Cancer
Peter J. Kushner, Ph.D.
University of California, San Francisco
Award type: IDEA
$150,000

Grape Seed as a Natural Breast Cancer Chemopreventive Agent
Melanie Ruth Palomares, M.D.
Beckman Research Institute of the City of Hope
Award type: IDEA
$252,236

Breast Cancer Risk Associated with High Mammographic Density
Thea D. Tlsty, Ph.D.
University of California, San Francisco
Award type: IDEA
$148,163