Study of the Apoptotic Phenotype as a Hallmark of Malignancy

Institution: University of California, San Francisco
Investigator(s): Nola Hylton, Ph.D. -
Award Cycle: 2003 (Cycle IX) Grant #: 9LB-0201 Award: $155,099
Award Type: Career Enrichment Award
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2003)
Molecular imaging is a rapidly evolving area of research that is likely to play a key role in translating new discoveries in genetics and molecular biology, to the treatment of human disease. Molecular imaging goes beyond traditional imaging of tissue anatomy to allow non-invasive characterization of disease processes. Defining the best imaging strategy requires an understanding of both the imaging technologies and the biologic mechanism under study. As the field of molecular imaging grows, it will become increasingly necessary to cross-train researchers involved in the study of human diseases in either the field of imaging or basic science. The PI’s present training and research is in the field of physics and breast cancer imaging. The aim of this project is to complement this expertise and allow training in the area of cancer molecular biology. It is anticipated that this training will enhance the PI’s ability to define questions and direct scientific studies in the area of molecular imaging of breast cancer.

The PI will participate in ongoing studies conducted in genetically manipulated mice, and cells derived from these mice, to determine the role, kinetics and temporal requirement for the Myc oncogene in driving tumor cell proliferation, de-differentiation, angiogenesis, invasion and apoptosis. The specific aims of the one-year project will address 1) in vitro (cell and genetic) analysis of the role of p53 in Myc-induced apoptosis using mouse embryo fibroblasts (MEFs) and explanted thymocytes, and 2) in vivo (mouse model) analysis of the role of p53 in delaying or regressing spontaneous and radiation induced lymphomas; and in the suppression of Myc-driven lymphomagenesis. These studies will employ a p53ERtam "knock-in" mouse model, and cells from these mice will be used to determine the biological efficacy and mechanism of p53 in mediating arrest and apoptotic responses to DNA damage and Myc activation. Although these experiments are preformed in a lymphoma tumor model, the techniques and rationale are directly applicable to breast cancer. Mice will be monitored weekly for lymphoma incidence by palpation of lymph nodes and lymphomagenesis, generalized tumor incidence and life span of animals will then be determined and compared with mice maintained in the absence of a tamoxifen derivative

This training will help the PI to more effectively bridge the fields of imaging and molecular markers of breast cancer. This will hopefully lead to improved imaging methods for detection, diagnosis and staging of breast disease.

Final Report (2006)
Note: This grant was extended 1-yr to complete the aims and funding.

Molecular and functional imaging is seen as an important component of the developing field of molecular medicine. Imaging has the potential to measure biological processes associated with cancer initiation and progression in vivo, and can thus provide a non-invasive method to characterize tumors and assess their response to treatment.

The goal of the Career Enrichment project has been to provide training in cancer biology using transgenic animal models for the PI, in support of her research objectives to develop better imaging methods for breast cancer patients, in particular those receiving pre-operative treatment using chemotherapy, hormonal agents, and newer targeted agents for treating locally-advanced breast cancer. The PI has participated in ongoing research projects in the laboratory of Gerard Evan at UCSF. The Evan laboratory has developed a series of genetically-defined mouse models of human cancer in which the oncogenic mutations driving proliferation and apoptosis can be acutely and reversibly “switched” on and off. In one model, the p53ERTAM knock-in mouse, p53 tumor suppression function can be “toggle” between p53 knock-out and wild-type status by denial or provision of 4-hydroxytamoxifen (OHT). The PI participated in these ongoing studies by learning basic laboratory and experimental techniques needed to address the scientific questions regarding the role of p53 in Myc-induced apoptosis. Preliminary imaging studies have also been undertaken using functional MRI techniques to assess the emergence and progression of tumors in carcinogen-induced glioma using the p53ERTAM knock-in mouse.

This research is directly applicable to breast cancer imaging at the molecular level. This enrichment experience allows the PI to better understand the basic science aspects associated with small animal imaging. Our future interests are to use novel approaches in animal studies as a bridge to envisioning and implementing molecular imaging for the detection, prognosis, and treatment evaluation of breast cancer in women.