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By Saijun Fan, MD, PhD
Breast cancer is the most common cancer among women. risk factors associated with breast cancer include inherited mutation in the breast cancer susceptibility genes BRCA1 and BRCA2; personal or family history of breast cancer; early onset of menstruation; late menopause; and never having had children or having a first child after age 30.
In recent years, epidemiological studies have suggested that alcohol consumption is associated with a high risk for breast tumorigenesis.1-3 In a pooled analysis of six prospective cohort studies examining dietary factors in breast cancer, increased alcohol intake correlated significantly with breast cancer risk.1 Moreover, the combination of alcohol consumption and postmenopausal estrogen replacement therapy synergistically enhanced the risk of cancer. In addition, several studies have reported that increased levels of circulating estrogen are associated with alcohol use; however, other studies have failed to demonstrate an increase in circulating or urinary estrogen in response to alcohol consumption.4 Increase of mammary gland carcinogenesis, change of carcinogen metabolism, and impaired immune defense also contribute to alcohol’s effects on breast cancer development and progression.5
Mechanism of Action
Alcohol is an etiologic agent for several different tumor types, including upper aerodigestive cancers (mouth, oropharynx, hypopharynx, and esophagus) and breast cancer. Alcohol is metabolized by the microsomal ethanol-oxidizing system, the activity of which is enhanced by chronic alcohol use. Alcohol is converted by alcohol dehydrogenase to acetaldehyde, which can induce DNA damage. This mechanism does not explain the specific association of alcohol and breast cancer, since alcohol-induced DNA damage should occur in all cell types. To date there are no compelling data to indicate a definitive mechanism for alcohol-induced breast cancer.
In our recent studies, we found that alcohol (ethanol) at physiologically relevant concentrations (£ blood levels associated with intoxication) causes: 1) down-regulation of the tumor suppressor gene BRCA1 in a dose-dependent manner; 2) significant up-regulation of estrogen receptor (ER)-a expression levels; and 3) a dose-dependent increase up to 10-fold in ER-a transcriptional activity in breast cancer cells.6 Additionally, we also found that alcohol consumption results in a significant increase in breast cancer cell motility, migration, and invasion, which is associated with decreased expression of the cell-cell adhesion molecules, E-cadherin and a-, b-, and g-catenins.6
Cell motility is an important component of the invasive cancer phenotype. In breast cancer, up-regulation of tumor cell motility and invasiveness is important during the transition from non-invasive cancer (ductal carcinoma in situ) to fully malignant invasive ductal carcinoma. Therefore, these novel findings provide in vitro evidence for a link between alcohol consumption and breast cancer. Based on these new findings, suggested mechanisms underlying the positive association between alcohol consumption and breast cancer risk include the potential influence of alcohol on steroid hormone levels and BRCA1 as a new inhibitor of ER-a.
ER belongs to the steroid/thyroid nuclear receptor family and is an estrogen-dependent transcriptional factor that regulates growth, development, differentiation, and homeostasis by binding to estrogen response elements in DNA to modulate the transcription of target genes, including progesterone receptors and trans- forming growth factors, in target organs, such as the breast and uterus. The definitive roles of ER in the dev-elopment and progression of breast cancer have been elucidated.7
Mutations of the breast cancer susceptibility gene BRCA1 (17q21) confer a high risk for breast and ovarian cancers.8 BRCA1 encodes an 1863 amino acid, 220 kDa phosphoprotein with an N-terminal RING finger domain that interacts with cell-cycle proteins, and an acidic C-terminal transcriptional activation domain. BRCA1 shows multiple biological activities in cell-cycle regulation, apoptosis, and DNA repair and recombination pathways that may be related to its tumor-suppressor functions. Recently, we found that BRCA1 regulates the transcriptional activity of the estrogen receptor, an important finding that may explain the linkage of BRCA1 mutations to breast cancer (i.e., loss of the ER-a inhibitory activity due to mutation of BRCA1 could lead to unopposed estrogenic stimulation of mammary epithelial cells, thus promoting the growth of already initiated mammary epithelial cell clones).9 The loss of BRCA1 inhibition of ER-a transcriptional activity also could contribute to sporadic breast cancers, since BRCA1 mRNA and protein levels frequently are decreased in sporadic invasive breast cancers, as compared with non-invasive cancers and benign tissue.10
Our studies link three risk factors—alcohol, ER, and BRCA1—to breast cancer development and progression. Our research also provides in vitro data establishing the molecular mechanisms by which alcohol may contribute to breast cancer by two important actions, up-regulation of ER activity and down-regulation of BRCA1. These actions form the basis for our proposed working model: alcohol consumption ® BRCA1¯ ® ER-a activity ® breast cancer development and progression. (Dr. Fan is an Assistant Professor, Albert Einstein College of Medicine, and Chief of the Laboratory of Molecular Oncology, Department of Radiation Oncology, Long Island Jewish Medical Center in New Hyde Park, NY.) v
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