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    BP1, a New Homeobox Gene: a Strong Potential Target for Therapy of Breast Cancer

    Scientific Abstract:
    BP1, a New Homeobox Gene: a Strong Potential Target for Therapy of Breast Cancer BACKGROUND. Finding the molecular changes associated with breast cancer is a high priority since genes involved in the initiation and progression of breast cancer may serve as markers for early diagnosis and targets for therapy, as well as markers for identification of residual disease. A newly cloned homeobox gene, BP1, is disproportionately expressed in invasive ductal breast tumors, and is a potential new target for therapy, based on observations that BP1 expression occurs in all ER negative tumors (p=0.03) and that 80% of invasive ductal breast tumors overexpress BP1, in contrast with BP1 expression in only 14% of normal breast tissues. Furthermore, 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 (p=0.04). African American women have a poorer prognosis than Caucasian women with the same grade tumor, so finding a target for therapy would be especially helpful to this group of women. Since BP1 is expressed at a similar frequency in all tumor grades, it appears to be activated early in malignancy or even in premalignant cells. Our data suggest that BP1 expression may be linked to cell survival since extinguishing BP1 expression in leukemia cells resulted in apoptosis (Preliminary Data). OBJECTIVE/HYPOTHESIS. The objective of these studies is to establish the utility of BP1 as a target in the therapy of breast cancer. We hypothesize that BP1 expression enhances malignant cell survival. SPECIFIC AIMS. In Aim 1, we will determine whether repression of BP1 results in apoptosis of breast cancer cells. In Aim 2, we will discover whether BP1 is part of a known apoptotic pathway. In Aim 3, specific molecular targets of BP1 will be identified. STUDY DESIGN. Aim 1: We will assess whether repression of BP1 results in apoptosis of breast cancer cells using cell lines stably transfected with a plasmid inducible for expression of small interfering RNA (siRNA) against BP1. Cells will be evaluated for effects of decreased BP1 levels on apoptosis, sensitivity to chemotherapeutic drugs, and transforming properties. Aim 2. The effect of BP1 on the death receptor and mitochondrial pathways of apoptosis will be measured using stable cell lines overexpressing BP1 and testing the activity of several caspases involved in each apoptotic pathway, as well as the percentage of apoptotic cells. Aim 3: We have identified an anti-apoptotic gene which is a possible target of BP1 protein, based on the presence of a consensus BP1 binding site in its promoter, the fact that BP1 protein binds to this DNA in vitro, and the observation that the gene is up-regulated when BP1 is overexpressed. To test the ability of BP1 to directly regulate this gene in vivo, we will use deletions of the promoter which have been fused to the Luciferase reporter gene. They will be co-transfected with a plasmid overexpressing BP1 to determine the functional significance of BP1 binding. Microarray chips will also be screened to examine the ability of BP1 to regulate genes involved in apoptotic, cell cycle and proliferation pathways. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH These studies will establish BP1 as an important, independent target in BP1 positive breast tumors if reduction or elimination of BP1 expression is sufficient to induce apoptosis in breast cancer cells. A reduction in transforming properties upon reducing BP1 levels would advance the idea that repression of BP1 would be attractive in the therapy of breast cancer patients either alone or in conjunction with other treatments. In addition, apoptosis is induced by many of the treatments used in the therapy of breast cancer, and aberrant regulation of apoptosis is believed to be a cause for resistance to treatment. We will discover whether BP1 levels affect the ability of breast cancer cells to undergo drug-induced apoptosis and thus whether targeting BP1 would be useful in conjunction with drug therapy, as well as predictive for response to drug treatment. We speculate that BP1 will prove to be directly involved in the regulation of apoptosis in breast cancer cells and thus a new target for therapy, particularly in the tumors of African American women and the difficult to treat estrogen receptor negative tumors.

    Lay Abstract:
    BP1, a New Homeobox Gene: a Strong Potential Target for Therapy of Breast Cancer Breast cancer is the leading cause of death among American women who are 35 to 55 years of age. Although increasingly more is known about the genes involved in breast cancer, better targets for therapy are still needed. We are studying a new gene called BP1, which is a potential target for therapy of breast cancer since BP1 was "turned on", or active in 100% of women whose breast cancer has the poorest prognosis. In fact, BP1 is active in 80% of breast tumors overall. BP1 expression also exhibits a racial disparity: 89% of the tumors of African American women are BP1 positive, compared with 57% of the tumors of Caucasian women. It is known that African American women with breast cancer are more likely to die than Caucasian women with breast cancer, but the reason for this is unknown. If BP1 could be used as a target for the treatment of African American women with breast cancer, this may increase their survival. What is the significance of BP1 activation in breast cancer? A clue comes from the fact that when we prevented BP1 activity in leukemia cells, where BP1 is also active, the cells died, suggesting that BP1 expression was necessary for cancer cell survival. If true for breast cancer cells, this would suggest a therapy for BP1 positive tumors: turn off the BP1 gene, thereby killing the malignant cells. Few normal cells have activated BP1, so this treatment would be quite specific for tumor cells. The main objective of this proposal is therefore to determine the possible utility of BP1 as a molecular target by establishing its role in the survival of breast cancer cells. Not only will we discover whether turning off BP1 will kill those cells, we will also determine whether enhanced BP1 activity, such as is seen in breast tumors, inhibits the ability of a chemotherapeutic drug to kill breast cancer cells and thus whether even reducing BP1 levels might allow a reduction in the drug concentrations used to treat patients. Using microarray technology, we will measure the effect of BP1 activation on changes in activation or repression of other genes associated with cell survival and resistance to cell death, as well as genes important in cell growth. Overall, these studies will establish the potential of BP1 as a molecular target for treatment of breast cancer.