Genetic Susceptibility to Breast Cancer

Institution: University of Southern California
Investigator(s): Brian Henderson, M.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0084 Award: $79,669
Award Type: IDEA
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (1995)
A substantial body of experimental, clinical and epidemiologic evidence indicates that hormones play a major role in the etiology of breast cancer. The known risk factors for breast cancer can be understood as measures of the cumulative exposure of the breast to estrogen and, perhaps, progesterone. Exposure to these hormones causes breast cells to grow and divide. We hypothesize that certain genes involved in the metabolism of estrogen in the body, such as those that convert estrogen from less active to more active forms, play important roles in breast cancer. We hypothesize that changes in the estrogen receptor (ER) gene, which works in concert with estrogen and other factors to signal breast cells to divide, are associated with breast cancer risk.

We propose to conduct a study to examine the possible associations between three genes and breast cancer in 400 women from an ethnically diverse cohort in Los Angeles County and Hawaii established in 1993. Fifty breast cancer cases and fifty controls between 45 and 74 years old from each of the following ethnic groups will be included in the study: African-American, Hispanic, Japanese, and

White. We have also collected data on family history, diet, and other lifestyle habits from these women via a mailed questionnaire. The questionnaire was translated into Spanish for study participants who were not English-speaking.

To date, very few studies have looked at the possible genetic components of breast cancer between and within different ethnic populations, and no study has focused on these specific genes. The significance of this proposed study lies in its multi disciplinary approach, focus on multiethnic populations and potential future impact. If this work identifies associations between these genes and breast cancer, it could be used to identify possible targets of intervention such as modification of estrogen metabolism within breast cells to slow or stop the proliferation of breast cancer cells.


Final Report (1996)
The known risk factors for breast cancer can be understood as measures of the cumulative exposure of the breast to estrogen and, perhaps, progesterone. Exposure to these hormones causes breast cells to grow and divide. We want to test the idea that certain genes involved in the metabolism of estrogen in the body, such as those that change estrogen from less active to more active forms, play important roles in breast cancer. We also hypothesize that changes in the estrogen receptor (ER) gene, which works together with estrogen and other factors to signal breast cells to divide, are associated with breast cancer risk. We are conducting a case-control study to examine the possible associations between three genes and breast cancer in 400 women from an ethnically diverse cohort in Los Angels County and Hawaii established in 1993. Fifty breast cancer cases and fifty controls (women without breast cancer, but similar in other important respects) between 45 and 74 years old from each of the following ethnic groups are included in the study: African-American, Hispanic, Japanese and White. We have also collected data on family history, diet and other lifestyle habits from these women via a mailed questionnaire. To date, we have established laboratory assays to look at changes in these three genes, completed the assays on approximately 200 cases and 200 controls, and begun to analyze the data.

We have found an important association between one gene, called CYP17, and breast cancer in our preliminary data analysis. This gene produces an enzyme (a protein that increases the rate of biochemical reactions in the body and in individual cells) called P450c17a , which functions at key points during the manufacture of estrogens in the ovaries. CYP17 contains a polymorphism, or change in the DNA sequence, that can be used to designate two forms of the gene (called alleles) A1 and A2. We found an increased risk of advanced breast cancer in women carrying an A2 allele. Women who carry the A2 allele were two and one-half times more likely to have advanced breast cancer than women with no A2 allele. We also found that CYP17 is associated with age at menarche (the age when a woman first starts ovulating and having menstrual periods). This is a significant finding because the establishment of regular ovulatory cycles may be the most critical reproductive determinant of breast cancer risk. The findings suggest that CYP17 genotype may be an important marker for the onset of ovulation and for advanced breast cancer risk.