Etiology and Prevention
Although our foundation of knowledge for the basic science aspects of breast cancer has expanded greatly over the past decade, gaps still remain in our strategies for large-scale prevention due to uncertainties over the underlying causes of the disease and their relative importance. There is an extensive list of factors associated with increased and decreased risk for breast cancer. However, the relative importance of diet, exercise, family history, pregnancy, alcohol, hormone replacement therapy, and other factors remains controversial. Two 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
Research Conclusions
Structural Characterization of Aromatase
Aromatase is the enzyme that converts androgen into estrogen. Aromatase inhibitors, which
block this synthesis of estrogen, are now widely used to treat hormone-responsive breast cancer in postmenopausal women. They are also being studied in the breast cancer prevention setting in high-risk women. Yanyan Hong, M.S., at the Beckman Research Institute of the City of Hope, Duarte, and colleagues are attempting to ascertain the three-dimensional structure of the
aromatase enzyme. This will allow them to gain insight into the precise way in which these drugs bind to and block the aromatase enzyme. This work could lead to the development of a more potent fourth-generation of aromatase inhibitors that could be used for the prevention and the treatment of hormone-responsive breast cancer. Findings from this research were published in New York Academy of Sciences 2006(1089)237; Molecular Endocrinology 2007(21)401; and Journal of Steroid Biochemistry and Molecular Biology 2007(106)8.
Breast Cancer Prevention with Phytochemicals in Mushrooms
Aromatase is a protein that makes estrogen, which plays a key role in the development of hormone-sensitive breast cancer. Oncologists use a class of drug called aromatase inhibitors to treat these types of tumors. Shiuan Chen, Ph.D, at the Beckman Research Institute of the City of Hope, Duarte, and colleagues previously showed that white button mushrooms (species Agaricus bisporus) contain chemicals that can suppress human aromatase activity. Dr. Chen and his team have now shown that, in a mouse model, these mushroom can turn off the genes that are involved in cell growth and energy production, and that they are able to do so even after the mushrooms are cooked. In addition, Dr. Chen and his team showed that white button mushrooms contain a type of fatty acid, called conjugated linoleic acid, which is an aromatase inhibitor; and that oral intake of mushroom extract decreases both tumor cell proliferation and tumor weight in mice. Based on these findings, a clinical trial that will test whether mushroom intake can inhibit estrogen production in postmenopausal breast cancer survivors will soon get underway at the City of Hope. Findings from this research were published in Cancer Research 2006(66)12026
Grape Seed as a Natural Breast Cancer Chemopreventive Agent
Aromatsase inhibitors are now widely used to treat hormone-response breast cancer in postmenopausal women; they are also being studied in the breast cancer prevention setting. Their effectiveness had led researchers to look for other chemicals that can also suppress aromatase. Melanie Ruth Palomares, M.D., M.S., at the Beckman Research Institute of the City of Hope, Duarte, previously demonstrated that grape seed extract acts like an aromatase inhibitor in mice. This grant allowed her to conduct a clinical trial that would investigate whether grape seed extract also acts like an aromatase inhibitor in healthy postmenopausal women. Dr. Palomares and her team enrolled 25 women in their trial and tested four different doses of grape seed extract, ranging from 50mg/day to 2,000mg/day. They are currently analyzing their data, and intend to present their findings when their work is completed. If Dr. Palomares finds that grape seed extract acts like an aromatase inhibitor in women, this research could lead to the introduction of a safe, inexpensive option for reducing breast cancer risk.
Targeted Chemoprevention in a Mouse Model for DCIS
Anti-estrogen treatments are currently used to reduce breast cancer risk in high-risk women. But anti-estrogen therapy is not effective in all patients. Jeffrey Gregg, M.D, at the University of California, Davis, investigated whether combining anti-estrogen therapy with an agent that promotes cell death would be more effective than anti-estrogen therapy alone. Dr. Gregg used a mouse model for DCIS to study the effect of the anti-estrogen treatment tamoxifen. This research indicated that tamoxifen reduced pre-neoplastic growth and decreased tumor incidence. It also showed that tamoxifen worked by decreasing cell proliferation. Next, Dr. Gregg used a mouse model for DCIS to study an agent that promotes cell death called rapamycin. This work showed that rapamycin reduces tumor incidence by inducing cell death. These findings suggest that this type of combination therapy might work better than an anti-estrogen therapy alone as a breast cancer prevention treatment. Findings from this research were published in Breast Cancer Research 2005(7)R881, Clinical Cancer Research 2006(12)2613, and BMC Cancer 2006(6)275.
Birth Characteristics and Breast Cancer in Young Women
Currently, only about 50% of breast cancer can be explained by known risk factors. Most of these risk factors are related to exposures to estrogens during adult life. Very little, however, is known about how factors experienced earlier in life affect later breast cancer risk. Peggy Reynolds, Ph.D., at the Northern California Cancer Center, Union City, used data from the U.S. census and the California Cancer Registry to investigate whether certain birth characteristics that are considered to be markers for high levels of in utero estrogen exposures are related to breast cancer risk in young women. Dr. Reynolds and her colleagues found, among other things, that maternal age and paternal age were the strongest predictors of breast cancer risk, and that women who were born post-term (42 weeks or later) had a significantly reduced risk of breast cancer. Dr. Reynolds and her team also found that women born to mothers living in higher socioeconomic neighborhoods had an increased risk of developing breast cancer, while region at birth was not associated with breast cancer risk. These findings were presented at the International Society for Environmental Epidemiology and International Society for Exposure Analysis (ISEE/ISEA) 2008 Joint Annual Conference and are in preparation for publication.
Androgen Receptor Gene and p21 Gene in Breast Cancer
Androgens, which are usually thought of as male hormones, have many important functions in the female body. These functions are both indirect (acting as a source of estrogen production) and direct (binding to the androgen receptor). Accumulating evidence suggests that the indirect effect (acting as a source of estrogen production) contributes to increased breast cancer risk, while the direct effect (binding to the androgen receptor) may reduce risk, with the overall effect being the balance between the two. Wei Wang, M.D., at the University of Southern California, Los Angeles, and colleagues previously found a relationship between a stronger type of androgen receptor and reduced breast cancer risk in a small group of African American women who had a mother or sister with breast cancer. This project allowed Dr. Wang and her team to study genetic variations in the androgen receptor in 1724 African American, Hispanic, and non-Hispanic white women and to investigate the relationship between a protein called p21 and breast cancer risk. They studied this protein because it is regulated by androgens and because it helps control normal and cancer cell growth. Dr. Wang and her team are now completing their data analysis.
Their findings have the potential to pave the way toward the development of new breast cancer prevention treatments.
Lifestyle Factors & Breast Cancer Prognosis in Asian Americans
Little is known about the influence of lifestyle factors on a woman’s breast cancer prognosis. Anna Wu, Ph.D., at the University of Southern California, Los Angeles, and colleagues conducted interviews with 1,463 Asian women who had taken part in a case-control study of breast cancer in Los Angeles to investigate whether prediagnostic dietary and non-dietary lifestyle factors were associated with breast cancer prognosis. Preliminary analyses of pre-diagnostic lifestyle factors found that the risk of mortality was not associated with intake of green tea or black tea. However, there was an increased risk seen in the women who had the highest weight and the lowest soy intake. Additional telephone interviews were conducted with 780 breast cancer patients to investigate whether there was a relationship between post-diagnostic dietary habits and the risk of recurrence or a second cancer. Preliminary analyses of these data suggest that the risk of recurrence or a second cancer is not associated with post-diagnostic body weight or intake of green tea or black tea. However, risk was lower among women who had a high intake of soy and seafood, and it was higher among those who ate a lot of red meat. Dr. Wu and her team are continuing to examine the role of soy as well as the combined effects of soy intake and use of tamoxifen on recurrence risk. This work will shed light on the relationship between dietary factors and breast cancer and could help identify dietary elements that may improve breast cancer outcomes. Results of this research were published in Nutrition and Cancer 2006(56)128.
Hereditary Breast Cancer and Novel Hispanic BRCA Mutations
Inherited mutations in the BRCA (BReast CAncer) genes are associated with 5-10% of breast cancer cases. Women with these mutations have up to an 85% risk of developing breast cancer in their lifetime. Little is known about the prevalence of the BRCA mutation in the Hispanic population. Jeffrey Weitzel, M.D., at the Beckham Research Institute of the City of Hope, Duarte, and colleagues developed a prototype genetic test for 18 different BRCA mutations common in the Hispanic population. Dr. Weitzel and his team found that a specific mutation called BRCA1 185delAG accounted for 11% of all the positive test results in this population. They are now revising the genetic test so that it can screen for 56 different common Hispanic BRCA mutations. The new test should be able to rapidly and inexpensively identify up to 90% of all BRCA mutations among high-risk Hispanic women undergoing genetic testing. Dr. Weitzel intends to use this test to pre-screen high-risk Hispanic patients at his clinic. If no mutation is found, a woman will go on to have the more expensive full BRCA gene test. By utilizing this unique Hispanic BRCA mutation panel, Dr. Weitzel and his colleagues will be able to reduce the cost associated with testing high-risk Hispanic individuals for BRCA mutations and be able to provide more extensive information to Hispanic women about their individual breast cancer risk. This research was published in Cancer, Epidemiology, Biomarkers and Prevention 2007(16)1615-20.
A Novel Biological Framework for the Role of Xenoestrogens
Exposure to estrogen mimicking compounds, called xenoestrogens, appears to play a role in cancer development. Shanaz Dairkee, Ph.D., at the California Pacific Medical Center Research Institute, San Francisco, developed a human cell model system to study the role of the xenoestrogen bisphenol A in malignant breast disease. Bisphenol A directly enters the human body by leaching out from polycarbonate plastic containers of food and beverages, and from epoxy resins used as dental sealants. Dr. Dairkee and her team identified gene signatures that reflect distinctive patterns of response to estrogen, progesterone, and bisphenol A; demonstrated that bisphenol A-induced genetic changes are similar to that of estrogen exposure; and showed that these changes promote cell survival. They also found that the genetic signature of bisphenol A was most often seen in aggressive, high-grade tumors. These findings suggest that analyzing this genetic signature in clinical tumor tissue could provide a reliable way to identify individuals who have been exposed to excessive xenoestrogen levels. It also could lead to the development of new breast cancer prevention treatments for women whose breast cells contain a genetic signature linked to bisphenol A exposure. Findings from this research were published in Cancer Research 2008(68)2076.
Breast Cancer Metastasis: A Heritable Trait?
Scientists have discovered a gene in mice that, when altered, causes their mammary cancers to spread to other organs (metastasize). Alice Whittemore, Ph.D., at Stanford University, Palo Alto, and colleagues used retrospective data from 743 female breast cancer patients in 242 families registered with the Fox Chase Cancer Center in Philadelphia and the Huntsman Cancer Institute in Salt Lake City to investigate whether humans can also inherit genetic mutations that increase their risk of having a breast cancer metastasize. Their research did not find any evidence to suggest that a family history of metastatic breast cancer contributes substantially to a breast cancer patient’s risk of metastasis.
The Hygiene Hypothesis and Breast Cancer Risk
Microbial exposures have been studied previously as part of the “hygiene hypothesis” to explain the causes of allergic and autoimmune diseases. This idea holds that reduced or delayed exposures to microbes, or living in a mostly disease-free, sanitized environment, hampers development of a healthy immune system. It is possible that an underdeveloped immune response might also influence breast cancer development by weakening immune responses against tumors, increasing estrogen production, or both. Christina Clarke Dur, Ph.D., at the Northern California Cancer Center, Union City, investigated whether women with breast cancer were less likely than healthy women to report certain exposures known to positively influence healthy immune system development. Preliminary analyses indicated an association between a history of mastitis and an increased risk of postmenopausal breast cancer. Dr. Clarke Dur and her colleagues intend to investigate this association further using data from the California Teachers Study. This research could help to jumpstart new efforts to study the role of immune system factors in breast cancer.
Grants in Progress: 2008 Breast Cancer Lymphedema: Role of Insulin Resistance/ Breast Cancer Risks in California Nail Salon Workers Circuit Training to Lower Breast Cancer Risk in Latina Teens Structural Characterization of Aromatase Tea, Genes, and Their Interactions on Breast |
Research Initiated in 2008 Antidepressant and Breast Cancer Drug Interactions FGFR2 Signaling in Human Breast Cancer Cells Folate, DNA Methylation and Breast Cancer Metastasis Genes in Hormone Metabolism Pathway and Breast Cancer Grapefruit, Hormones, and Postmenopausal Breast Pesticide and Gene Interactions in Latina Farm Workers Prognostic Implications of DNA Glycation in Breast Cancer |
