> Research & Grants
> Grants Program
> Research Grants
> Research Grants Awarded
A Murine Model of Breast Cancer-Associated Lymphedema: Genome-Wide Transcriptional Profiling for the Study of Lymphedema Pathobiology, Cellular Signaling Mechanisms and Mechanisms of Therapeutic Lymphangiogenesis
Background: Lymphedema of the upper extremity represents an important component of the biology and natural history of breast cancer. Lymphedema is a common, important, and often devastating consequence of successful surgical and adjuvant therapy of breast malignancies. Despite recent surgical advances, up to 15-30% of breast cancer survivors have evidence of impaired lymphatic function. The presence and severity of lymphedema has a substantial impact on the quality of life and the perception of well-being in breast cancer survivors, yet there is no cure, and current treatment options are limited.
Recently, we have successfully demonstrated the potential to invoke therapeutic lymphangiogenesis in an animal model of breast cancer-associated lymphedema. Our preliminary studies suggest that the biology of acquired lymphedema and its response to molecular therapy can be further elucidated through genome-wide transcriptional profiling of the target tissues.
Objective/Hypothesis: The biology of lymphedema is complex and still poorly understood, but molecular interventions to prevent or treat breast cancer-associated lymphedema show great promise. The profound structural abnormalities of lymphedematous tissues reflect a complex multi-cellular response to lymph stagnation. This disease is amenable to study through transcriptional profiling, using microarray techniques. This approach can be utilized to identify mechanisms of disease and refine targets for molecular therapy. We propose to apply genome-wide transcriptional profiling to the study of lymphedematous skin before and after VEGF-C-induced therapeutic lymphangiogenesis.
Specific Aims: Transcriptional profiling of this animal model system can address the following specific aims: 1. to further characterize the subsidiary molecular responses that comprise the complex structural and functional alterations of acquired lymphedema; 2. to elucidate the signaling mechanisms that invoke the lymphatic repair response; 3. to identify novel candidate genes in order to further refine molecular strategies in therapeutic lymphangiogenesis for breast cancer-associated lymphedema.
Study Design: We have modeled breast cancer-associated lymphedema in the mouse tail through targeted, surgical lymphatic disruption. Skin will be harvested before 1 and after  therapeutic lymphangiogenesis with recombinant human VEGF-C and compared to normal skin . Administration of VEGF-C to the normal tail  and surgical sham intervention  provide experimental controls. RNA will be isolated from the harvested skin of all 5 groups and hybridized to a mouse transcriptome array representing ~43,000 features (~25,000 unique genes). Identified transcriptional targets will be verified and further characterized through quantitative real time RT-PCR. The disease will be studied at 3 distinct time points after surgery (24 hours, 14 days, 10 weeks) to explore the temporal biology of the disease and its amenability to therapy in the face of varying degrees of chronicity.
Potential Outcomes and Benefits of the Research. Therapeutic lymphangiogenesis holds great promise for breast cancer-associated lymphedema. Our preliminary studies in this model suggest that it has significant potential to enhance comprehension of its complex biology and to identify novel candidate genes that will enhance the development of clinically applicable molecular interventions in this disease.
Lymphedema of the arm is an important aspect of the disease of breast cancer and its natural history. Lymphedema is a common and often devastating consequence of successful, life-preserving breast cancer treatment. Even in the face of recent surgical refinements, up to 15-30% of breast cancer survivors continue to experience some degree of lymphedema. The presence and severity of lymphedema has a substantial impact on the quality of life and the perception of well-being in breast cancer survivors, yet there is no cure. Current treatment options are helpful, but limited.
With current advances in early detection and effective adjuvant therapies, many women diagnosed with breast cancer can now expect survival that is similar to age-matched women without breast cancer. Therefore, effective prevention and management of life-altering complications, such as lymphedema,have assumed increasing importance. Of greatest promise for breast cancer-associated lymphedema is the recent demonstration, in our laboratory and others, that administration of biological growth factors can stimulate new vessel growth and help to undo the damage that occurs when the lymph circulation is impaired through the breast cancer and its treatments. In order to implement such strategies in patients, we must first better comprehend the complex biology of lymphedema and its response to biological repair mechanisms.
Complex diseases of this type can often best be explored through appropriate animal models. We have developed an experimental animal model of breast cancer-associated lymphedema in the mouse and have demonstrated the success of growth factor therapy at reversing lymphatic damage in the model.
We now proposed to further characterize breast cancer associated lymphedema, and its response to growth factor therapies through newer, sophisticated molecular techniques, called 'genome-wide transcriptional profiling', that permit us to characterize the ways in which the diseased tissues respond, in a molecular fashion, to the stress of impaired lymph flow. We isolate RNA from the lymphedema tissues and characterize the thousands of genes that are expressed in response to disease. By using these techniques, it should be possible to further characterize the biology of lymphedema and to identify novel target genes that would allow a refined, targeted treatment approach. Growth factor-based treatments thus would be aimed at specific aspects of the problem, ideally with minimal undesired effects.
The ultimate goal of this project is to provide treatment alternatives for millions of breast cancer survivors whose quality of life and perception of health is hampered by the presence of lymphedema. Growth factors therapies hold great promise. Our preliminary studies suggest that the proposed project will enhance and accelerate the ability to develop these treatment approaches and, ultimately, apply them to the human disease.