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    Research Grants Awarded

    Human Papillomavirus Infection As A Potential Cause of Breast Cancer

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    The complete etiology of breast cancer is unclear. Important risk factors include family history, hormones, and cigarette smoking. These risk factors are shared by another female malignancy, namely cervical cancer. In cancer of the cervix the most important risk factor is infection with any one of a group of human papillomavirus (HPV) types, known as high-risk HPVs. A number of recent studies have detected HPV DNA in breast tumors suggesting HPV might have a role in the development of breast cancer. As modern approaches to identify carcinogens involve initiating mechanistic studies that evaluate the molecular actions of agents in the appropriate cells, our goal is to determine if human mammary epithelial cells (HMEC) are susceptible to infection by three HPV types detected in breast tissues, HPV11, 16 and 31. HPV gene expression in infected cells is very low and helps the virus evade the immune system and persist. Thus, we have developed two specific aims to test our hypothesis that HPV can infect HMEC in vitro. First, we will determine viral functions in transfected HMEC where a large fraction of the cells contain HPV genomes. Second, we will use this information to determine if HMEC can be infected with HPV11, 16, or 31. The Specific Aims are: 1). Determine the extent of viral genome replication and the pattern of viral gene expression in HMEC following the nuclear transfection of viral genomes into the cells; 2). Assess the ability of HMEC to become infected, express HPV early transcripts, and maintain viral DNA following the exposure of the cells to purified virions. Transfection of HMEC in Aim 1 will permit us to determine the spectrum of early viral RNAs expressed in HMEC, which will allow a more specific and sensitive measure of infection in Aim 2. Transfection will also help us to evaluate whether the HPV genomes can provide normal mortal HMEC with an extended life span or immortality, important measures of malignant conversion. We will then determine whether and how long the viral DNA can persist in HMEC as another measure of transformation. However, the key to this program and its innovation lie in our ability to test whether HMEC are susceptible to infection by purified HPV virions, and if so, how long infection persists. This information is crucial to a clearer understanding of the role HPV might play in causing breast cancer in vivo.

    Lay Abstract:
    The complete cause of breast cancer is unclear. Important factors include family history, hormones, and cigarette smoking. These factors are shared by another female malignancy: cervical cancer. In cancer of the cervix the most important factor is infection with any one of a group of human papillomaviruses (HPVs). A number of recent studies have detected genetic material (DNA) from HPVs in breast tumors suggesting HPV might have a role in causing breast cancer. Modern approaches to identify cancer-causing agents involve experiments aimed at understanding the functions of such agents at the molecular level and using the appropriate cells; in this case human mammary epithelial cells (HMEC). Therefore, our goal is to determine if HMEC are susceptible to infection by three different HPV types detected in breast tissues. HPV activities in infected cells are very low and this helps the virus hide from the immune system and remain in the cells. Thus, we have developed two specific aims to test our hypothesis that HPV can infect HMEC. First, we will flood HPV DNA into a predominant number of HMEC so that we can readily determine viral activities. Second, we will use this information to determine if the three HPV viruses can infect HMEC, which will occur at much lower frequency. The Specific Aims are: 1). Determine the extent of viral life cycle activities in HMEC following the introduction of viral DNA into the cells; 2). Assess the ability of HMEC to become infected and permit viral activities following HMEC exposure to pure virus particles. Direct introduction of viral DNA into HMEC in Aim 1 will permit us to determine the spectrum of viral activities in HMEC, which will allow a more specific and sensitive measure of actual infection in Aim 2. Direct DNA transfer will also help us to evaluate if the HPV DNA can provide normal HMEC, which have a finite life, with an extended life span or immortality, important measures of malignant cell conversion. We will then determine whether and how long the viral DNA can persist in HMEC as another measure of cancer progression. However, the key to this program and its innovation lie in our ability to test whether HMEC are susceptible to infection by purified HPV virus particles, and if so, how long infection lasts in the cells. This information is crucial to a clearer understanding of the role HPV might play in causing breast cancer in women.