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Research Grants Awarded
Development of BMP4 as a Therapy for Metastatic Breast Cancer
In a recent study, bone morphogenic protein-4 (BMP4) was found to be reduced in tumors with high metastatic potential. Preliminary data has shown that re-expression of BMP4 in a highly metastatic mammary tumor line can suppress metastasis to several sites (including lung and bone) and dramatically improve survival of mice bearing this tumor. BMP4 is a member of the transforming growth factor-beta (TGF-ß) superfamily of cytokines and is involved in a number of developmental processes such as differentiation, haematopoiesis, tissue patterning and polarity. BMP4 was initially identified as a bone-repair factor, which may be advantageous if used as a therapeutic for osteolytic bone diseases, such as metastatic breast cancer. It is the intention of this project to determine whether BMP4 is predictive of metastatic disease and whether administration of BMP4 or intervention in the BMP4 signalling pathway can be translated into a clinically useful treatment for metastatic breast cancer. The specific aims of the project are: (1) To use two different approaches to assess whether BMP4 therapy can suppress metastasis and prolong survival of mice bearing a highly metastatic mammary tumor that spreads to lymph nodes, lung, bone and other tissues following primary tumor growth in the mammary gland. (2) To establish whether the expression of BMP4 or its receptor BMP-RII is predictive of metastatic disease in human breast cancer using archival tissues. (3) To determine the underlying mechanism by which BMP4 inhibits breast cancer metastasis. This project has enormous potential to benefit patients suffering from metastatic disease, which is currently incurable. If our hypothesis is correct, the BMP4 signalling pathway could be the basis of a curative therapy.
The majority of deaths due to breast cancer are a result of the formation of secondary tumors (metastasis) that arise in distant organs such as lymph nodes, lung and bone. Metastatic spread to these organs leads to debilitating complications, such as respiratory problems, spinal cord compression, bone pain and fractures. Current therapies are palliative, aiming to relieve the symptoms caused by metastases. To achieve curative therapies, a better understanding of the genetics that underlie the process of metastasis is required. Using a novel mouse model of breast cancer metastasis, we have identified several genes that can potentially inhibit metastasis. One of these genes, bone morphogenic protein 4 (BMP4) holds great promise for anti-metastasis therapy. Recent results from our laboratory suggest that tumors with high BMP4 expression do not spread as readily as tumors that lack BMP4 expression. When the levels of BMP4 expression are increased in aggressive breast cancers, we observe a striking reduction in the extent of metastasis and a dramatic increase in survival of mice bearing these tumors. These data strongly implicate BMP4 as a critical mediator in the pathway that leads to metastasis formation. The studies proposed here will test whether the administration of BMP4 protein can prevent metastasis from occurring and will explore the molecular basis for this inhibition. Further, we will assess the importance of BMP4 in human breast cancer using archival tumor tissues with clinical follow-up to ascertain whether BMP4 can be used as a prognostic marker for metastatic disease. This project has enormous potential for patients with advanced breast cancer as it offers the possibility of a new curative therapy for this currently incurable disease.