The steroid hormone estrogen plays a critical role in the development of human breast cancer. Anti-estrogen therapy has been believed to be an effective treatment of breast cancer over more than 100 years. However, the anti-estrogen therapy is still restricted mainly because of that estrogen has fundamental physiological actions and a wide range of beneficial effects on bone, brain, cardiovascular and other targeted tissues. Thus, it has become a primary focus of inquiry to understand how estrog ....The steroid hormone estrogen plays a critical role in the development of human breast cancer. Anti-estrogen therapy has been believed to be an effective treatment of breast cancer over more than 100 years. However, the anti-estrogen therapy is still restricted mainly because of that estrogen has fundamental physiological actions and a wide range of beneficial effects on bone, brain, cardiovascular and other targeted tissues. Thus, it has become a primary focus of inquiry to understand how estrogen specifically functions in breast cancer but not in normal tissues. Estrogen serves different functions involving a series of biochemical reactions called signal transduction pathways that can couple estrogen to a specific function, such as cancer formation. We have recently found that a enzyme named sphingosine kinase (SK) activation triggers a novel signal transduction pathway in regulation of cell growth and tumour formation, and that this pathway was activated by estrogen in human breast cancer cells. Thus, we seek to identify how estrogen activate SK and how they contribute to the development of breast cancer. It will ultimately provide a potential target for therapeutic intervention and may yield new compounds that have clinical benefit for anti-breast-cancer.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
CHAPERONES IN BREAST CANCER AND ESTROGEN RECEPTOR FUNCTION
Funder
National Health and Medical Research Council
Funding Amount
$256,573.00
Summary
Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor res ....Resistance to hormone therapy in breast cancer is due to adaptations of estrogen signalling mechanisms that result in ERa activation causing growth. So, in the search for new treatments, we are looking for ways to remove ERa from the breast cancer cell. Our study addresses this major issue by focussing on Hsp90 molecular chaperone machinery that is essential for ERa function and in particular immunophilin 'helper' cochaperones that form part of receptor-Hsp90 complexes and fine-tune receptor responses to hormone. Through a novel mode of action, coumarin-based Hsp90 inhibitors disrupt Hsp90 dimerization causing receptor release and subsequent depletion. We will confirm this novel mechanism for new, high affinity Hsp90 inhibitors and determine which can best interfere with estrogen signalling, either alone or in combination with antiestrogen therapies in the treatment of hormone-dependent cancers. Our study has the potential to pin point the site of action of the immunophilins in ERa to a proline in a region critical for ligand-induced receptoractivation. We will determine the role of the immunophilins and this active-site proline residue in modulating receptor stability and function. Aberrant expression of receptor-associated immunophilins appears linked to endocrine resistance and metastasis in breast cancer. Our study will profile the expression of these chaperones in well defined breast cancer tissue microarrays, and has the potential to identify them as informative biomarkers in the treatment of the disease.Read moreRead less
Wnt-5a Signalling - A Novel Therapy For Triple Negative And Tamoxifen Resistant Breast Cancer Patients
Funder
National Health and Medical Research Council
Funding Amount
$330,534.00
Summary
Breast cancer is the most common cancer in women. Commonly used drugs target the estrogen receptor (ER). However, one third of breast cancer patients lack ER, and do not respond to treatment. Cancers that lack ER also lack a gene called Wnt5a, which is linked to better prognosis. We have shown that fixing Wnt5a can restore ER allowing cells to respond to Tamoxifen. We would now test this in animals, in the hope of developing a new drug for breast cancer patients currently with limited options.
Linking Estrogens, Prostatitis And Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$291,309.00
Summary
Prostatitis is very common and a significant health issue that affects men from their 20's. Estrogens promote inflammation and inflammation is associated with the development of cancer. If this study links estrogens, prostatitis and prostate cancer, we can provide better treatment for prostatitis, thus preventing progression to prostate cancer
Cognitive Enhancement In Schizophrenia Via Selective Oestrogen Receptor Modulator.
Funder
National Health and Medical Research Council
Funding Amount
$396,380.00
Summary
Cognitive dysfunction in schizophrenia is resistant to treatment and related to poor community functioning and quality of life. In spite of the widely appreciated magnitude of the problem, there is still a critical gap in our knowledge concerning treatments to reverse these cognitive deficits. The proposed research is significant because it will clarify the role of hormones and genes in relation to cognitive deficits in schizophrenia and it may help patients improve their level of functioning.