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    Research Grants Awarded

    BP1 Expression, Apoptosis, and Breast Cancer Aggressiveness in African American Women

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    BACKGROUND. Tumors of African American (AA) women with breast cancer are more aggressive than tumors of Caucasian women, resulting in a poorer prognosis. A homeobox gene, BP1, may be an important factor in their aggressive tumors since 89% of the tumors of AA women express BP1 mRNA compared with 57% of the tumors of Caucasian women, and expression of BP1 has been linked to tumor aggressiveness. High BP1 levels directly stimulate the bcl-2 gene, leading to increased cell survival, suggesting a mechanism for BP1 action in breast cancer. OBJECTIVE/HYPOTHESIS . Our objective is to determine whether BP1 protein (pBP1) is up-regulated in the tumors of AA women, thereby stimulating anti-apoptotic genes, leading to decreased cell death and shorter disease-specific survival. We hypothesize that BP1 expression enhances malignant cell survival in the tumors of AA women by inhibiting apoptosis. AIMS . Our aims are to study tumors of AA women to determine the frequency of pBP1 positivity (Aim 1); establish whether key apoptotic proteins are aberrantly regulated (Aim 2); investigate whether BP1 mRNA levels affect apoptotic pathways (Aim 3). STUDY DESIGN. Aim 1: Measure pBP1 in tumors of 240 AA and 240 Caucasian women; determine the association between BP1 positivity, race and outcome. Aim 2: Assess the protein expression of three key genes in the apoptotic pathway by immunostaining the same tumors as in Aim 1. Determine associations between expression of these genes, BP1, race and outcome. Aim 3: Microdissect tumors to assess whether higher BP1 mRNA correlates with changes in apoptotic gene expression, race and outcome. POTENTIAL OUTCOMES AND BENEFITS. These studies will help establish BP1 as an important factor in the aggressive tumors of AA women if any of the following are found in tumors of AA women: more frequent expression of pBP1 or higher BP1 mRNA levels; association of BP1 expression with regulation of apoptotic genes; association of BP1 expression with poor outcome. If BP1 is involved in the regulation of apoptosis in breast cancer in AA women, it would be an excellent target for therapy. Reducing BP1 may increase tumor sensitivity to drugs since resistance to cell death is associated with resistance to treatment. If BP1 expression is related to outcome, assessing BP1 upon diagnosis might be useful in determining the optimal treatment regimen. Thus, these experiments could lead to significant advances in the treatment of AA women with breast cancer.

    Lay Abstract:
    African American women with breast cancer die at twice the rate as Caucasian women with breast cancer. Researchers believe that tumors of African Americans are more aggressive than those of Caucasians and that this is due, at least in part, to genetic differences between the two groups. We are studying a gene called BP1 that may be an important factor in the aggressiveness of African American women’s tumors. We suspect this since BP1 is active in 80% of breast tumors, and BP1 expression exhibits a racial disparity --89% of the tumors of African American women are BP1 positive, compared with 57% of the tumors of Caucasian women. How does BP1 activation change cells? Our data show that when BP1 is turned on it affects other genes, resulting in reduced cell death. The latter translates into increased cell survival, a hallmark of cancer cells. The main objectives of this study are to determine whether activation of BP1 enhances cancer cell survival in the tumors of African American women by inhibiting cell death, and whether BP1 positivity predicts a shorter survival time. We will examine tumors from 240 African American women and from 240 Caucasian women to compare BP1 effects. Using sensitive assays, we will measure the level of BP1 in tumors, allowing us to assess whether the level of BP1 activity is a predictor of survival. This will tell us whether more BP1 is associated with more aggressive tumors. Moreover, we will examine other genes known to be involved in reducing cell death to determine if a relationship exists between their activity and the activity of BP1. In short, these studies will help to establish whether BP1 is an important factor in the aggressive tumors of African American women. Our results could have important clinical applications: (i) If the amount of BP1 present in a tumor is related to survival, assessing BP1 levels upon diagnosis would aid in determining the optimal treatment rather than the current one-size-fits-all approach.(ii) If BP1 is directly involved in preventing cell death in tumors, it would be an excellent target for therapy. Reducing BP1 may kill tumor cells or shorten their life span. (iii) Because resistance to cell death is associated with resistance to treatment, reducing BP1 may increase sensitivity of a tumor to drugs. Thus, the data anticipated from these experiments have the potential of making a significant difference in treating the aggressive tumors seen in African American women.