Understanding The Role Of RAS Mutations In Thyroid Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$463,854.00
Summary
My fellowship will examine the association of RAS mutations in thyroid cancer. RAS proteins are the most mutated in cancer and I will investigate how they work in thyroid cancer. RAS mutated thyroid cancer is more likely to cause death. This grant will be based in the pioneering lab of Prof Fagin at Memorial Sloan Kettering Cancer Center and the Garvan Institute of Medical Research. It is hoped by understanding these mutations, new treatments for thyroid cancer can be developed.
REGULATION OF ANDROGEN RECEPTOR And ErbB-2 GENE EXPRESSION IN PROSTATE CANCER: ROLE OF THE HU PROTEINS
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate can ....Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate cancer cells. Thus the AR is a major target for therapy. Even when the disease is unresponsive to androgen withdrawal, the AR is present. Furthermore, we know that these PCa cells recruit other androgen-independent pathways to activate growth. One such pathway is the erbB-2 signaling cascade, which drives the cells towards proliferation. Proteins that bind to RNA, the cellular messenger, are playing an increasing role in the biology of cancer. HuR, a member of the Hu-Elav family, augments growth of colon cancer cells, and is associted with poor outcomes in ovarian and brain malignancies. We have recently identified the first proteins that bind to AR and erbB-2 mRNA. Remarkably, HuR binds to both sequences. Furthermore, HuD, another member of the Hu-Elav family which is normally only found in the brain, is aberrantly expressed in human PCa. In this Project we will determine the effects of these proteins on the growth of human PCa cells in culture and in whole animal models. We will also evaluate their presence in a large array of human PCa specimens. It is envisaged that this work will develop novel links between the two pathways bringing them together in a previously unrecognised manner. We also aim to solve the molecular structure of Hu proteins bound to the AR mRNA. Outcomes of the work will include new potential tests for prostate cancer and improved prognosis prediction, and establishment of a foundation for the development of novel targets for therapy.Read moreRead less
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less