Computational Bioinformatics & Bio-imaging Laboratory (CBIL)


 
 

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Center of Excellence: Molecular Epidemiology and Mechanisms for Breast Carcinogenesis (DAMD17-03-1-0448)
 
 

Background: Many of the contributing risk factors to breast cancer are known, but many are not. One established risk factor is alcohol drinking. In fact, it also is among the most consistently documented risk factor other than familial and hormonal risk factors. The reasons why alcohol drinking causes breast cancer have received limited attention, even with its importance and that alcohol drinking can be a mechanistic paradigm for other etiologies. There is good evidence to support the study of a multifactorial relationship between alcohol drinking and breast cancer. For example, we know that: 1) the enzymes for ethanol metabolism are present in the breast; 2) that alcohol affects estrogen metabolism, estrogen levels, estrogen responses and breast density (an intermediate biomarker for breast cancer risk); 3) alcohol decreases the clearance of estrogen replacement therapy; 4) ethanol metabolism induces oxidative damage; 5) acetaldehyde, an ethanol metabolite, causes DNA damage; 6) ethanol and acetaldehyde inhibit DNA repair and; 6) alcohol consumption affects folic acid intake and utilization, DNA methylation, gene regulation and mutations.

Objective/Hypotheses: Our major hypotheses are that ethanol affects breast cancer risk through: 1) perturbation of estrogen metabolism and response; 2) increased oxidative stress and damage to DNA and proteins; 3) mutagenesis by acetaldehyde; 4) an interaction with folate intake and resultant changes in methylation and mutations as they relate to inactivation of tumor suppressor genes; 5) modulation by interindividual differences in host response due to genetic polymorphisms and diet. We also hypothesize that: 6) some of the above mechanisms will play greater roles than others. Definitive conclusions will come from examining the evidence from complementary and corroborative study designs.

Specific Aims: We will study the effects of drinking, diet and genetic polymorphisms involving the above hypothesized pathways. The Aims are: 1) to use DNA and tumor blocks from a previously conducted breast cancer case-control study of 3,152 women to study gene-environment interactions for breast cancer risk; 2) to conduct a study of mammographic breast density in 1064 Caucasian and African American women, where breast density is considered an intermediate biomarker of breast cancer risk; 3) to conduct an intensive biomarker study of breast tissue from 100 Caucasian and African American cancer-free women undergoing reduction mammoplasty, which will demonstrate the effects of alcohol before cancer develops and; 4) to utilize several different experimental animal models that will document the roles of the mechanistic pathways.

Study design: Our Center will use a multidisciplinary approach that can answer questions in an integrated fashion by 4 institutions. Our research strategy bridges basic to population science, and follows along the lines of a causality assessment. Among the different, but corroborative study designs listed above, we will investigate the same hypotheses using mostly the same biomarkers and study instruments, all in relation to alcohol drinking. We will study women with and without cancer, rat models for tumor initiation and promotion, and knock-out mice. The animal studies mimic human alcohol and dietary exposures. The studies mostly use the same well-established and/or novel biomarkers, such as gene promoter hypermethylation, mitochondrial mutations, microarrays, p53 mutations, comparative genomic hybridization, protein analysis for adducts and metabolizing genes, markers of oxidative damage, estrogen receptor analyses, digital mammography, and MRI of mammary glands. Genotyping for the pathways will be done across all the human studies.

Relevance: The attributable risk for alcohol drinking is about 17,000 breast cancers per year. While seemingly low compared to the total number of new cases (although it is not), this is a documented and modifiable risk factor. It affects about 4 times more women than those in high risk families. Just as the study of BRCA mutations allows for a broader understanding of breast cancer, we can use alcohol as a paradigm for breast carcinogenesis and other preventable causes of breast cancer as well. Definitive studies on breast carcinogenesis would lead to improved public health recommendations, allow for women to make individual choices about lifestyle and risk, place alcohol drinking into a broader context of interactions with risk factors such diet, hormone replacement therapy, etc., and lead to more rationale prevention strategies.

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